Heteroaryl and benzyl amide compounds

ABSTRACT

Compounds of formula I 
     
       
         
         
             
             
         
       
     
     wherein R 1 , R 2 , R 4 , R 5 , A, B, D and n are as defined, and pharmaceutically acceptable salts thereof, processes for their preparation, their use as pharmaceuticals and pharmaceutical compositions comprising them.

PRIORITY TO RELATED APPLICATIONS

This application claims the benefit of European Application No.06101370.2, filed Feb. 7, 2006, which is hereby incorporated byreference in its entirety.

The present invention relates to novel benzamide and heteroarenecarboxamide derivatives, processes for their preparation, their use aspharmaceuticals and to pharmaceutical compositions comprising them.

More particularly, the present invention provides in a first aspect acompound of formula I

wherein

-   R¹ is C₁-C₆alkyl, halo-C₁-C₆alkyl, halo-C₁-C₆alkoxy,    C₃-C₈cycloalkyl, halo-C₃-C₈cycloalkyl or tri-C₁-C₆alkylsilyl;-   R² is hydrogen or a group

-   -   wherein

-   R⁶ and R⁷ are independently hydrogen, C₁-C₆alkyl, halo-C₁-C₆alkyl,    halogen, C₃-C₈cycloalkyl, OH or halo-C₁-C₆alkoxy;

-   R⁸ and R⁹ are independently hydrogen, C₁-C₆alkyl, halo-C₁-C₆alkyl,    halogen, C₃-C₈cycloalkyl, OH or halo-C₁-C₆alkoxy;

-   X is CR¹² or N;

-   Y is CH or N;    -   wherein X and Y are not N at the same time;

-   R¹² is hydrogen, C₁-C₆alkyl, halo-C₁-C₆alkyl, halogen,    C₃-C₈cycloalkyl, OH or halo-C₁-C₆alkoxy;

-   R⁵ is hydrogen, C₁-C₆alkyl, halo-C₁-C₆alkyl, halogen,    C₃-C₈cycloalkyl, OH or halo-C₁-C₆alkoxy;

-   R⁴ is hydrogen, or is C₁-C₆alkyl, halo-C₁-C₆alkyl, halogen,    C₃-C₈cycloalkyl, OH or halo-C₁-C₆alkoxy when at least one of R³, R⁵,    R¹⁰ and R¹¹ is not hydrogen;

-   A is CR¹⁰ or N;

-   B is CR¹¹ or N;

-   D is CR³ or N;

-   wherein —B=A- and -A=D- are not —N═N—;

-   R³ is hydrogen, C₁-C₆alkyl, halo-C₁-C₆alkyl, halogen,    C₃-C₈cycloalkyl, OH or halo-C₁-C₆alkoxy;

-   R¹⁰ is hydrogen, or is C₁-C₆alkyl, halo-C₁-C₆alkyl, halogen,    C₃-C₈cycloalkyl, OH or halo-C₁-C₆alkoxy, when at least one of R³,    R⁴, R⁵ and R¹¹ is not hydrogen;

-   R¹¹ is hydrogen or is C₁-C₆alkyl, halo-C₁-C₆alkyl, halogen,    C₃-C₈cycloalkyl, OH or halo-C₁-C₆alkoxy, when at least two of R³,    R⁴, R⁵ and R¹⁰ are not hydrogen;    wherein at least two of R³, R⁴, R⁵, R¹⁰ and R¹¹ are not hydrogen;    and    n is 1, 2 or 3;    and pharmaceutically acceptable salts thereof.

Examples of C₁-C₆alkyl include branched and straight-chain monovalentsaturated aliphatic hydrocarbon radicals of one to six carbon atoms,e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert.-butyl, theisomeric pentyls and the isomeric hexyls.

Examples of halogen include fluorine, chlorine, bromine and iodine.

Examples of halo-C₁-C₆alkyl include C₁-C₆alkyl groups as defined abovewherein at least one of the hydrogen atoms of the C₁-C₆alkyl group isreplaced by a halogen atom, e.g. fluoro or chloro, e.g. trifluoromethyl,difluoromethyl, fluoromethyl,1,2,2,2-tetrafluoro-1-trifluoromethyl-ethyl, pentafluoroethyl andchlorodifluoromethyl.

Examples of halo-C₁-C₆alkoxy include alkoxy groups of formulaO-C₁-C₆alkyl wherein at least one of the hydrogen atoms of the alkoxygroup is replaced by a halogen atom, e.g. fluoro or chloro, e.g.trifluoromethoxy, difluoromethoxy, fluoromethoxy andchlorodifluoromethoxy.

Examples of C₃-C₈cycloalkyl include saturated carbocyclic groupscontaining from 3 to 8 carbon atoms, such as cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

Examples of halo-C₃-C₈cycloalkyl include 1-fluorocyclobutyl.

Examples of tri-C₁-C₆alkylsilyl include trimethylsilyl.

The term “pharmaceutically acceptable salts” refers to those salts whichretain the biological effectiveness and properties of the free bases orfree acids, which are not biologically or otherwise undesirable. Thesalts are formed with inorganic acids such as hydrochloric acid,hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and thelike, preferably hydrochloric acid, and organic acids such as aceticacid, propionic acid, glycolic acid, pyruvic acid, oxylic acid, maleicacid, malonic acid, salicylic acid, succinic acid, fumaric acid,tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid,salicylic acid, N-acetylcystein and the like. In addition these saltsmay be prepared from addition of an inorganic base or an organic base tothe free acid. Salts derived from an inorganic base include, but are notlimited to, the sodium, potassium, lithium, ammonium, calcium, magnesiumsalts and the like. Salts derived from organic bases include, but arenot limited to salts of primary, secondary, and tertiary amines,substituted amines including naturally occurring substituted amines,cyclic amines and basic ion exchange resins, such as isopropylamine,trimethylamine, diethylamine, triethylamine, tripropylamine,ethanolamine, lysine, arginine, N-ethylpiperidine, piperidine, polymineresins and the like. The compound of formula I can also be present inthe form of zwitterions. Particularly preferred pharmaceuticallyacceptable salts of compounds of formula I are the hydrochloride salts.

The compounds of formula I can also be solvated, e.g. hydrated. Thesolvation can be effected in the course of the manufacturing process orcan take place e.g. as a consequence of hygroscopic properties of aninitially anhydrous compound of formula I (hydration). The termpharmaceutically acceptable salts also includes physiologicallyacceptable solvates.

“Isomers” are compounds that have identical molecular formulae but thatdiffer in the nature or the sequence of bonding of their atoms or in thearrangement of their atoms in space. Isomers that differ in thearrangement of their atoms in space are termed “stereoisomers”.Stereoisomers that are not mirror images of one another are termed“diastereoisomers”, and stereoisomers that are non-superimposable mirrorimages are termed “enantiomers”, or sometimes optical isomers. A carbonatom bonded to four nonidentical substituents is termed a “chiralcenter”.

In one embodiment the present invention provides a compound of formula Iwherein R¹ is C₁-C₆alkyl, halo-C₁-C₆alkyl, C₃-C₈cycloalkyl,halo-C₃-C₈cycloalkyl or tri-C₁-C₆alkylsilyl. In another embodiment thepresent invention provides a compound of formula I wherein R¹ isC₁-C₆alkyl. In still another embodiment the present invention provides acompound of formula I wherein R¹ is butyl. In still another embodimentthe present invention provides a compound of formula I wherein R¹ istert-butyl.

In one embodiment the present invention provides a compound of formula Iwherein R² is hydrogen.

In another embodiment the present invention provides a compound offormula I wherein R² is a group (a). In another embodiment the presentinvention provides a compound of formula I wherein R² is a group (a)wherein R⁶ and R⁷ are independently halo-C₁-C₆alkyl or halogen. In stillanother embodiment the present invention provides a compound of formulaI wherein R² is a group (a) wherein R⁶ halo-C₁-C₆alkyl and R⁷ ishalogen. In still another embodiment the present invention provides acompound of formula I wherein R² is a group (a) wherein R⁶ is CF₃ and R⁷is Cl.

In another embodiment the present invention provides a compound offormula I wherein R² is a group (b). In another embodiment the presentinvention provides a compound of formula I wherein R² is a group (b)wherein R⁸ and R⁹ are independently hydrogen, halo-C₁-C₆alkyl, halogen,C₃-C₈cycloalkyl or halo-C₁-C₆alkoxy. In still another embodiment thepresent invention provides a compound of formula I wherein R² is a group(b) wherein R⁸ and R⁹ are independently hydrogen, CF₃, Cl, F,cyclopropyl or OCF₃. In still another embodiment the present inventionprovides a compound of formula I wherein R² is a group (b) wherein R⁸ ishydrogen, CF₃, Cl, F, cyclopropyl or OCF₃. In another embodiment thepresent invention provides a compound of formula I wherein R² is a group(b) wherein R⁸ and R⁹ are independently hydrogen, C₁-C₆alkyl,halo-C₁-C₆alkyl, halogen, C₃-C₈cycloalkyl or halo-C₁-C₆alkoxy. In stillanother embodiment the present invention provides a compound of formulaI wherein R² is a group (b) wherein R⁸ and R⁹ are independentlyhydrogen, CH₂CH₃, (CH₂)₂CH₃, CH(CH₃)₂, CF₃, Br, Cl, F, cyclopropyl orOCF₃. In still another embodiment the present invention provides acompound of formula I wherein R² is a group (b) wherein R⁸ is hydrogen,CH₂CH₃, (CH₂)₂CH₃, CH(CH₃)₂, CF₃, Br, Cl, F, cyclopropyl or OCF₃. Instill another embodiment the present invention provides a compound offormula I wherein R² is a group (b) wherein R⁹ is hydrogen, Cl or F. Instill another embodiment the present invention provides a compound offormula I wherein R² is a group (b) wherein R⁹ is hydrogen or F.

In another embodiment the present invention provides a compound offormula I wherein R² is a group (b) wherein X is CR¹². In still anotherembodiment the present invention provides a compound of formula Iwherein R² is a group (b) wherein X is CR¹² wherein R¹² is hydrogen,C₁-C₆alkyl, halo-C₁-C₆alkyl, halogen or halo-C₁-C₆alkoxy. In stillanother embodiment the present invention provides a compound of formulaI wherein R² is a group (b) wherein X is CR¹² wherein R¹² is hydrogen,C₁-C₆alkyl, halo-C₁-C₆alkyl or halogen. In still another embodiment thepresent invention provides a compound of formula I wherein R² is a group(b) wherein X is CR¹² wherein R¹² is hydrogen or halogen. In stillanother embodiment the present invention provides a compound of formulaI wherein R² is a group (b) wherein X is CR¹² wherein R¹² is hydrogen,Cl or F. In still another embodiment the present invention provides acompound of formula I wherein R² is a group (b) wherein X is CR¹²wherein R¹² is hydrogen, C₁-C₆alkyl, halo-C₁-C₆alkyl, halogen,C₃-C₈cycloalkyl or halo-C₁-C₆alkoxy. In still another embodiment thepresent invention provides a compound of formula I wherein R² is a group(b) wherein X is CR¹² wherein R¹² is hydrogen, C₁-C₆alkyl,halo-C₁-C₆alkyl, halogen or C₃-C₈cycloalkyl. In still another embodimentthe present invention provides a compound of formula I wherein R² is agroup (b) wherein X is CR¹² wherein R¹² is hydrogen, halogen orC₃-C₈cycloalkyl. In still another embodiment the present inventionprovides a compound of formula I wherein R² is a group (b) wherein X isCR¹² wherein R¹² is hydrogen, Cl, F or cyclopropyl.

In another embodiment the present invention provides a compound offormula I wherein R² is a group (b) wherein X is or N and Y is CH.

In another embodiment the present invention provides a compound offormula I wherein R² is a group (b) wherein Y is CH.

In another embodiment the present invention provides a compound offormula I wherein R² is a group (b) wherein Y is N and X is CR¹².

In another embodiment the present invention provides a compound offormula I wherein A is CR¹⁰. In still another embodiment the presentinvention provides a compound of formula I wherein A is CR¹⁰ wherein R¹⁰is hydrogen, or is halo-C₁-C₆alkyl, halogen, C₃-C₈cycloalkyl or OH, whenat least one of R³, R⁴, R⁵ and R¹¹ is not hydrogen. In still anotherembodiment the present invention provides a compound of formula Iwherein A is CR¹⁰ wherein R¹⁰ is halo-C₁-C₆alkyl or halogen, when atleast one of R³, R⁴, R⁵ and R¹¹ is not hydrogen. In still anotherembodiment the present invention provides a compound of formula Iwherein A is CR¹⁰ wherein R¹⁰ is CF₃ or Cl, when at least one of R³, R⁴,R⁵ and R¹¹ is not hydrogen.

In another embodiment the present invention provides a compound offormula I wherein A is N and B and D are not N.

In another embodiment the present invention provides a compound offormula I wherein B is CR¹¹. In another embodiment the present inventionprovides a compound of formula I wherein B is CR¹¹ wherein R¹¹ ishydrogen or is halogen, when at least two of R³, R⁴, R⁵ and R¹⁰ are nothydrogen. In another embodiment the present invention provides acompound of formula I wherein B is CR¹¹ wherein R¹¹ is hydrogen or is For Cl, when at least two of R³, R⁴, R⁵ and R¹⁰ are not hydrogen. Instill another embodiment the present invention provides a compound offormula I wherein B is CR¹¹ wherein R¹¹ is hydrogen.

In another embodiment the present invention provides a compound offormula I wherein B is N and A is not N.

In another embodiment the present invention provides a compound offormula I wherein D is CR³. In still another embodiment the presentinvention provides a compound of formula I wherein D is CR³ wherein R³is hydrogen.

In another embodiment the present invention provides a compound offormula I wherein D is N.

In another embodiment the present invention provides a compound offormula I wherein R⁵ is hydrogen, halo-C₁-C₆alkyl, halogen or OH. Instill another embodiment the present invention provides a compound offormula I wherein R⁵ is hydrogen, halo-C₁-C₆alkyl or halogen. In stillanother embodiment the present invention provides a compound of formulaI wherein R⁵ is hydrogen or halogen. In still another embodiment thepresent invention provides a compound of formula I wherein R⁵ ishydrogen or F.

In another embodiment the present invention provides a compound offormula I wherein R⁴ is hydrogen, or is C₁-C₆alkyl, halo-C₁-C₆alkyl orhalogen when at least one of R³, R⁵, R¹⁰ and R¹¹ is not hydrogen. Instill another embodiment the present invention provides a compound offormula I wherein R⁴ is halo-C₁-C₆alkyl or halogen and at least one ofR³, R⁵, R¹⁰ and R¹¹ is not hydrogen. In still another embodiment thepresent invention provides a compound of formula I wherein R⁴ is CF₃ orCl and at least one of R³, R⁵, R¹⁰ and R¹¹ is not hydrogen. In stillanother embodiment the present invention provides a compound of formulaI wherein R⁴ is C₁-C₆alkyl, halo-C₁-C₆alkyl or halogen and at least oneof R³, R⁵, R¹⁰ and R¹¹ is not hydrogen. In still another embodiment thepresent invention provides a compound of formula I wherein R⁴ is CH₂CH₃,CF₃ or Cl and at least one of R³, R⁵, R¹⁰ and R¹¹ is not hydrogen.

The present invention provides compounds of formula I wherein at leasttwo of R³, R⁴, R⁵, R¹⁰ and R¹¹ are not hydrogen.

In another embodiment the present invention provides a compound offormula I wherein n is 1.

In one embodiment the present invention provides a compound of formula Iwherein

-   R¹ is C₁-C₆alkyl, halo-C₁-C₆alkyl, halo-C₁-C₆alkoxy,    C₃-C₈cycloalkyl, halo-C₃-C₈cycloalkyl or tri-C₁-C₆alkylsilyl;-   R² is hydrogen;-   R⁵ is hydrogen, C₁-C₆alkyl, halo-C₁-C₆alkyl, halogen,    C₃-C₈cycloalkyl, OH or halo-C₁-C₆alkoxy;-   R⁴ is hydrogen, or is C₁-C₆alkyl, halo-C₁-C₆alkyl, halogen,    C₃-C₈cycloalkyl, OH or halo-C₁-C₆alkoxy when at least one of R³, R⁵,    R¹⁰ and R¹¹ is not hydrogen;-   A is CR¹⁰ or N;-   B is CR¹¹ or N;-   D is CR³ or N;-   wherein —B=A- and -A=D- are not —N═N—;-   R³ is hydrogen, C₁-C₆alkyl, halo-C₁-C₆alkyl, halogen,    C₃-C₈cycloalkyl, OH or halo-C₁-C₆alkoxy;-   R¹⁰ is hydrogen, or is C₁-C₆alkyl, halo-C₁-C₆alkyl, halogen,    C₃-C₈cycloalkyl, OH or halo-C₁-C₆alkoxy, when at least one of R³,    R⁴, R⁵ and R¹¹ is not hydrogen;-   R¹¹ is hydrogen or is C₁-C₆alkyl, halo-C₁-C₆alkyl, halogen,    C₃-C₈cycloalkyl, OH or halo-C₁-C₆alkoxy, when at least two of R³,    R⁴, R⁵ and R¹⁰ are not hydrogen;    wherein at least two of R³, R⁴, R⁵, R¹⁰ and R¹¹ are not hydrogen;    and    n is 1, 2 or 3;    and pharmaceutically acceptable salts thereof.

In one embodiment the present invention provides a compound of formula Iwherein

-   R¹ is C₁-C₆alkyl, halo-C₁-C₆alkyl, halo-C₁-C₆alkoxy,    C₃-C₈cycloalkyl, halo-C₃-C₈cycloalkyl or tri-C₁-C₆alkylsilyl;-   R² is a group

-   -   wherein R⁶ and R⁷ are independently hydrogen, C₁-C₆alkyl,        halo-C₁-C₆alkyl, halogen, C₃-C₈cycloalkyl, OH or        halo-C₁-C₆alkoxy;

-   R⁵ is hydrogen, C₁-C₆alkyl, halo-C₁-C₆alkyl, halogen,    C₃-C₈cycloalkyl, OH or halo-C₁-C₆alkoxy;

-   R⁴ is hydrogen, or is C₁-C₆alkyl, halo-C₁-C₆alkyl, halogen,    C₃-C₈cycloalkyl, OH or halo-C₁-C₆alkoxy when at least one of R³, R⁵,    R¹⁰ and R¹¹ is not hydrogen;

-   A is CR¹⁰ or N;

-   B is CR¹¹ or N;

-   D is CR³ or N;

-   wherein —B=A- and -A=D- are not —N═N—;

-   R³ is hydrogen, C₁-C₆alkyl, halo-C₁-C₆alkyl, halogen,    C₃-C₈cycloalkyl, OH or halo-C₁-C₆alkoxy;

-   R¹⁰ is hydrogen, or is C₁-C₆alkyl, halo-C₁-C₆alkyl, halogen,    C₃-C₈cycloalkyl, OH or halo-C₁-C₆alkoxy, when at least one of R³,    R⁴, R⁵ and R¹¹ is not hydrogen;

-   R¹¹ is hydrogen or is C₁-C₆alkyl, halo-C₁-C₆alkyl, halogen,    C₃-C₈cycloalkyl, OH or halo-C₁-C₆alkoxy, when at least two of R³,    R⁴, R⁵ and R¹⁰ are not hydrogen;    wherein at least two of R³, R⁴, R⁵, R¹⁰ and R¹¹ are not hydrogen;    and    n is 1, 2 or 3;    and pharmaceutically acceptable salts thereof.

In one embodiment the present invention provides a compound of formula Iwherein

-   R¹ is C₁-C₆alkyl, halo-C₁-C₆alkyl, halo-C₁-C₆alkoxy,    C₃-C₈cycloalkyl, halo-C₃-C₈cycloalkyl or tri-C₁-C₆alkylsilyl;-   R² is a group

-   -   wherein

-   R⁸ and R⁹ are independently hydrogen, C₁-C₆alkyl, halo-C₁-C₆alkyl,    halogen, C₃-C₈cycloalkyl, OH or halo-C₁-C₆alkoxy;

-   X is CR¹² or N;

-   Y is CH or N;    -   wherein X and Y are not N at the same time;

-   R¹² is hydrogen, C₁-C₆alkyl, halo-C₁-C₆alkyl, halogen,    C₃-C₈cycloalkyl, OH or halo-C₁-C₆alkoxy;

-   R⁵ is hydrogen, C₁-C₆alkyl, halo-C₁-C₆alkyl, halogen,    C₃-C₈cycloalkyl, OH or halo-C₁-C₆alkoxy;

-   R⁴ is hydrogen, or is C₁-C₆alkyl, halo-C₁-C₆alkyl, halogen,    C₃-C₈cycloalkyl, OH or halo-C₁-C₆alkoxy when at least one of R³, R⁵,    R¹⁰ and R¹¹ is not hydrogen;

-   A is CR¹⁰ or N;

-   B is CR¹¹ or N;

-   D is CR³ or N;

-   wherein —B=A- and -A=D- are not —N═N—;

-   R³ is hydrogen, C₁-C₆alkyl, halo-C₁-C₆alkyl, halogen,    C₃-C₈cycloalkyl, OH or halo-C₁-C₆alkoxy;

-   R¹⁰ is hydrogen, or is C₁-C₆alkyl, halo-C₁-C₆alkyl, halogen,    C₃-C₈cycloalkyl, OH or halo-C₁-C₆alkoxy, when at least one of R³,    R⁴, R⁵ and R¹¹ is not hydrogen;

-   R¹¹ is hydrogen or is C₁-C₆alkyl, halo-C₁-C₆alkyl, halogen,    C₃-C₈cycloalkyl, OH or halo-C₁-C₆alkoxy, when at least two of R³,    R⁴, R⁵ and R¹⁰ are not hydrogen;    wherein at least two of R³, R⁴, R⁵, R¹⁰ and R¹¹ are not hydrogen;    and    n is 1, 2 or 3;    and pharmaceutically acceptable salts thereof.

In one embodiment the present invention provides a compound of formula Iwherein

-   R¹ is C₁-C₆alkyl, halo-C₁-C₆alkyl, halo-C₁-C₆alkoxy,    C₃-C₈cycloalkyl, halo-C₃-C₈cycloalkyl or tri-C₁-C₆alkylsilyl;-   R² is hydrogen or a group

-   -   wherein

-   R⁶ and R⁷ are independently hydrogen, C₁-C₆alkyl, halo-C₁-C₆alkyl,    halogen, C₃-C₈cycloalkyl, OH or halo-C₁-C₆alkoxy;

-   R⁸ and R⁹ are independently hydrogen, C₁-C₆alkyl, halo-C₁-C₆alkyl,    halogen, C₃-C₈cycloalkyl, OH or halo-C₁-C₆alkoxy;

-   X is CR¹² or N;

-   Y is CH or N;    -   wherein X and Y are not N at the same time;

-   R¹² is hydrogen, C₁-C₆alkyl, halo-C₁-C₆alkyl, halogen,    C₃-C₈cycloalkyl, OH or halo-C₁-C₆alkoxy;

-   R⁵ is hydrogen, C₁-C₆alkyl, halo-C₁-C₆alkyl, halogen,    C₃-C₈cycloalkyl, OH or halo-C₁-C₆alkoxy;

-   R⁴ is hydrogen, or is C₁-C₆alkyl, halo-C₁-C₆alkyl, halogen,    C₃-C₈cycloalkyl, OH or halo-C₁-C₆alkoxy when at least one of R³, R⁵,    R¹⁰ and R¹¹ is not hydrogen;

-   A is CR¹⁰;

-   B is CR¹¹ or N;

-   D is CR³ or N;

-   R³ is hydrogen, C₁-C₆alkyl, halo-C₁-C₆alkyl, halogen,    C₃-C₈cycloalkyl, OH or halo-C₁-C₆alkoxy;

-   R¹⁰ is hydrogen, or is C₁-C₆alkyl, halo-C₁-C₆alkyl, halogen,    C₃-C₈cycloalkyl, OH or halo-C₁-C₆alkoxy, when at least one of R³,    R⁴, R⁵ and R¹¹ is not hydrogen;

-   R¹¹ is hydrogen or is C₁-C₆alkyl, halo-C₁-C₆alkyl, halogen,    C₃-C₈cycloalkyl, OH or halo-C₁-C₆alkoxy, when at least two of R³,    R⁴, R⁵ and R¹⁰ are not hydrogen;    wherein at least two of R³, R⁴, R⁵, R¹⁰ and R¹¹ are not hydrogen;    and    n is 1, 2 or 3;    and pharmaceutically acceptable salts thereof.

In one embodiment the present invention provides a compound of formula Iwherein

-   R¹ is C₁-C₆alkyl, halo-C₁-C₆alkyl, halo-C₁-C₆alkoxy,    C₃-C₈cycloalkyl, halo-C₃-C₈cycloalkyl or tri-C₁-C₆alkylsilyl;-   R² is hydrogen or a group

-   -   wherein    -   R⁶ and R⁷ are independently hydrogen, C₁-C₆alkyl,        halo-C₁-C₆alkyl, halogen, C₃-C₈cycloalkyl, OH or        halo-C₁-C₆alkoxy;    -   R⁸ and R⁹ are independently hydrogen, C₁-C₆alkyl,        halo-C₁-C₆alkyl, halogen, C₃-C₈cycloalkyl, OH or        halo-C₁-C₆alkoxy;    -   X is CR¹² or N;    -   Y is CH or N;    -   wherein X and Y are not N at the same time;    -   R¹² is hydrogen, C₁-C₆alkyl, halo-C₁-C₆alkyl, halogen,        C₃-C₈cycloalkyl, OH or halo-C₁-C₆alkoxy;

-   R⁵ is hydrogen, C₁-C₆alkyl, halo-C₁-C₆alkyl, halogen,    C₃-C₈cycloalkyl, OH or halo-C₁-C₆alkoxy;

-   R⁴ is hydrogen, or is C₁-C₆alkyl, halo-C₁-C₆alkyl, halogen,    C₃-C₈cycloalkyl, OH or halo-C₁-C₆alkoxy when at least one of R³, R⁵    and R¹¹ is not hydrogen;

-   A is N;

-   B is CR¹¹;

-   D is CR³;

-   R³ is hydrogen, C₁-C₆alkyl, halo-C₁-C₆alkyl, halogen,    C₃-C₈cycloalkyl, OH or halo-C₁-C₆alkoxy;

-   R¹¹ is hydrogen or is C₁-C₆alkyl, halo-C₁-C₆alkyl, halogen,    C₃-C₈cycloalkyl, OH or halo-C₁-C₆alkoxy, when at least two of R³,    R⁴, R⁵ and R¹⁰ are not hydrogen;    wherein at least two of R³, R⁴, R⁵, R¹⁰ and R¹¹ are not hydrogen;    and    n is 1, 2 or 3;    and pharmaceutically acceptable salts thereof.

In one embodiment the present invention provides a compound of formula Iwherein

-   R¹ is C₁-C₆alkyl, halo-C₁-C₆alkyl, halo-C₁-C₆alkoxy,    C₃-C₈cycloalkyl, halo-C₃-C₈cycloalkyl or tri-C₁-C₆alkylsilyl;-   R² is hydrogen or a group

-   -   wherein    -   R⁶ and R⁷ are independently hydrogen, C₁-C₆alkyl,        halo-C₁-C₆alkyl, halogen, C₃-C₈cycloalkyl, OH or        halo-C₁-C₆alkoxy;    -   R⁸ and R⁹ are independently hydrogen, C₁-C₆alkyl,        halo-C₁-C₆alkyl, halogen, C₃-C₈cycloalkyl, OH or        halo-C₁-C₆alkoxy;    -   X is CR¹² or N;    -   Y is CH or N;    -   wherein X and Y are not N at the same time;    -   R¹² is hydrogen, C₁-C₆alkyl, halo-C₁-C₆alkyl, halogen,        C₃-C₈cycloalkyl, OH or halo-C₁-C₆alkoxy;

-   R⁵ is hydrogen, C₁-C₆alkyl, halo-C₁-C₆alkyl, halogen,    C₃-C₈cycloalkyl, OH or halo-C₁-C₆alkoxy;

-   R⁴ is hydrogen, or is C₁-C₆alkyl, halo-C₁-C₆alkyl, halogen,    C₃-C₈cycloalkyl, OH or halo-C₁-C₆alkoxy when at least one of R³, R⁵,    R¹⁰ and R¹¹ is not hydrogen;

-   A is CR¹⁰;

-   B is CR¹¹ or N;

-   D is CR³;

-   R³ is hydrogen, C₁-C₆alkyl, halo-C₁-C₆alkyl, halogen,    C₃-C₈cycloalkyl, OH or halo-C₁-C₆alkoxy;

-   R¹⁰ is hydrogen, or is C₁-C₆alkyl, halo-C₁-C₆alkyl, halogen,    C₃-C₈cycloalkyl, OH or halo-C₁-C₆alkoxy, when at least one of R³,    R⁴, R⁵ and R¹¹ is not hydrogen;

-   R¹¹ is hydrogen or is C₁-C₆alkyl, halo-C₁-C₆alkyl, halogen,    C₃-C₈cycloalkyl, OH or halo-C₁-C₆alkoxy, when at least two of R³,    R⁴, R⁵ and R¹⁰ are not hydrogen;    wherein at least two of R³, R⁴, R⁵, R¹⁰ and R¹¹ are not hydrogen;    and    n is 1, 2 or 3;    and pharmaceutically acceptable salts thereof.

In one embodiment the present invention provides a compound of formula Iwherein

-   R¹ is C₁-C₆alkyl;-   R² is a group

-   -   wherein    -   R⁸ and R⁹ are independently hydrogen, halo-C₁-C₆alkyl, halogen,        C₃-C₈cycloalkyl or halo-C₁-C₆alkoxy;    -   X is CR¹²;    -   Y is CH;    -   R¹² is hydrogen or halogen;

-   R⁵ is hydrogen or halogen;

-   R⁴ is halo-C₁-C₆alkyl or halogen;

-   A is CR¹⁰;

-   B is CR¹¹ or N;

-   D is CR³;

-   R³ is hydrogen;

-   R¹⁰ is halo-C₁-C₆alkyl or halogen;

-   R¹¹ is hydrogen;    and    n is 1, 2 or 3;    and pharmaceutically acceptable salts thereof.

In one embodiment the present invention provides a compound of formula Iwherein

-   R¹ is C₁-C₆alkyl;-   R² is a group

-   -   wherein    -   R⁸ and R⁹ are independently hydrogen, halo-C₁-C₆alkyl, halogen,        C₃-C₈cycloalkyl or halo-C₁-C₆alkoxy;    -   X is CR¹²;    -   Y is CH;    -   R¹² is hydrogen, halogen or C₃-C₈cycloalkyl;

-   R⁵ is hydrogen or halogen;

-   R⁴ is C₁-C₆alkyl, halo-C₁-C₆alkyl or halogen;

-   A is CR¹⁰;

-   B is CR¹¹ or N;

-   D is CR³;

-   R³ is hydrogen;

-   R¹⁰ is halo-C₁-C₆alkyl or halogen;

-   R¹¹ is hydrogen;    and    n is 1, 2 or 3;    and pharmaceutically acceptable salts thereof.

In addition to the foregoing the present invention also provides aprocess for the production of a compound of formula I

wherein

-   R¹ is C₁-C₆alkyl, halo-C₁-C₆alkyl, halo-C₁-C₆alkoxy,    C₃-C₈cycloalkyl, halo-C₃-C₈cycloalkyl or tri-C₁-C₆alkylsilyl;-   R² is hydrogen or a group

-   -   wherein    -   R⁶ and R⁷ are independently hydrogen, C₁-C₆alkyl,        halo-C₁-C₆alkyl, halogen, C₃-C₈cycloalkyl, OH or        halo-C₁-C₆alkoxy;    -   R⁸ and R⁹ are independently hydrogen, C₁-C₆alkyl,        halo-C₁-C₆alkyl, halogen, C₃-C₈cycloalkyl, OH or        halo-C₁-C₆alkoxy;    -   X is CR¹² or N;    -   Y is CH or N;    -   wherein X and Y are not N at the same time;    -   R¹² is hydrogen, C₁-C₆alkyl, halo-C₁-C₆alkyl, halogen,        C₃-C₈cycloalkyl, OH or halo-C₁-C₆alkoxy;

-   R³ and R⁵ are independently hydrogen, C₁-C₆alkyl, halo-C₁-C₆alkyl,    halogen, C₃-C₈cycloalkyl, OH or halo-C₁-C₆alkoxy;

-   R⁴ is hydrogen, or is C₁-C₆alkyl, halo-C₁-C₆alkyl, halogen,    C₃-C₈cycloalkyl, OH or halo-C₁-C₆alkoxy when at least one of R³, R⁵,    R¹⁰ and R¹¹ is not hydrogen;

-   A is CR¹⁰ or N;

-   B is CR¹ or N;

-   D is CR³ or N; wherein —B=A- and -A=D- are not —N═N—;

-   R¹⁰ is hydrogen, or is C₁-C₆alkyl, halo-C₁-C₆alkyl, halogen,    C₃-C₈cycloalkyl, OH or halo-C₁-C₆alkoxy, when at least one of R³,    R⁴, R⁵ and R¹¹ is not hydrogen;

-   R¹¹ is hydrogen or is C₁-C₆alkyl, halo-C₁-C₆alkyl, halogen,    C₃-C₈cycloalkyl, OH or halo-C₁-C₆alkoxy, when at least two of R³,    R⁴, R⁵ and R¹⁰ are not hydrogen;    wherein at least two of R³, R⁴, R⁵, R¹⁰ and R¹¹ are not hydrogen;    and    n is 1, 2 or 3;    which process comprises reacting an acid derivative, a compound of    formula II

wherein R⁴, R⁵, A, B and D have the above meanings and W is hydroxy,OLi, ONa, OK or halogen, e.g. Cl,with a secondary amine derivative, a compound of formula III

wherein R¹, R² and n have the above meanings.

If carboxylic acids (W═OH) or carboxylate salts (W═OLi, ONa, OK) offormula II are used in this process, standard peptide coupling reagentscan be applied to activate the acid prior to the coupling reaction.Typically, the acid derivative II (R═OH, OLi, ONa, OK) is mixed with acoupling reagent such as EDC or EDC.HCl, DCC, HBTU or TBTU in an inertsolvent such as N,N-dimethylformamide, dimethylacetamide (DMA) ordichloromethane (DCM) together with the appropriate secondary aminederivative III. Optionally a base (e.g. N,N-diisopropylethyl amine,triethylamine, N-methyl morpholine) and/or 1-hydroxybenzotriazole (HOBT)can be added. The reaction mixture is stirred for 1 to 24 h at atemperature of about −30° C. to about 70° C. (e.g. ambient temperature).

Alternatively, acid chlorides (W═Cl) can be reacted with secondary aminederivatives III to obtain formula (I) compounds, using standardprotocols.

Acid derivatives of formula II are commercially available or can beprepared as described in the example section.

Secondary amines of the general formula III can be synthesized bystandard methods. They may be synthesized as outlined below.

Compounds of formula III

wherein

-   R¹ is C₁-C₆alkyl, halo-C₁-C₆alkyl, halo-C₁-C₆alkoxy,    C₃-C₈cycloalkyl, halo-C₃-C₈cycloalkyl or tri-C₁-C₆alkylsilyl;-   R² is hydrogen or a group

-   -   wherein    -   R⁶ and R⁷ are independently hydrogen, C₁-C₆alkyl,        halo-C₁-C₆alkyl, halogen, C₃-C₈cycloalkyl, OH or        halo-C₁-C₆alkoxy;    -   R⁸ and R⁹ are independently hydrogen, C₁-C₆alkyl,        halo-C₁-C₆alkyl, halogen, C₃-C₈cycloalkyl, OH or        halo-C₁-C₆alkoxy;    -   X is CR¹² or N;    -   Y is CH or N;    -   wherein X and Y are not N at the same time;    -   R¹² is hydrogen, C₁-C₆alkyl, halo-C₁-C₆alkyl, halogen,        C₃-C₈cycloalkyl, OH or halo-C₁-C₆alkoxy; and        n is 1, 2 or 3;        may be prepared by reductive amination of a benzaldehyde        derivative, a compound of formula IV

wherein R¹ is as defined above,with an amine, a compound of formula V

wherein R² and n are as defined above.

The necessary starting amines and aldehydes are commercially availableor are synthesized using standard methods as e.g. described in theexample section.

Secondary amines III may alternatively be synthesized from amidederivatives, compounds of formula VII

wherein R¹, R² and n are as defined above.

Amide derivatives, compounds of formula VII are available by thecoupling of benzoic acid derivatives, compounds of formula VI

wherein R¹ is as defined above,with a compound of formula V.

The necessary starting benzoic acids are commercially available or maybe synthesized using standard methods as e.g. described in the examplesection.

The following abbreviations are used: RT: room temperature; THF:tetrahydrofuran; DMF: N,N-dimethylformamide; DCM: dichloromethane

In general, the nomenclature used in this Application is based onAUTONOM™ v.4.0, a Beilstein Institute computerized system for thegeneration of IUPAC systematic nomenclature.

Aldehydes (Acids) (Compounds of Formula IV and VI): Example S1-APreparation of 4-cyclopropyl benzaldehyde

To a solution of 1-bromo-4-cyclopropylbenzene [synthesized in analogy toa procedure described in J. Org. Chem. 1976, 41, 2262-2266] (1.58 g,8.04 mmol) in THF at −78° C. was added n-BuLi (5.08 ml, 1.6M solution inhexane, 8.11 mmol) and the reaction mixture was stirred at −78° C. for10 min. DMF (1.25 ml, 16.08 mmol) was then added and the reactionmixture was stirred at −78° C. for 15 min. The reaction mixture was thenwarmed to 0° C. slowly (over 2 h) and stirred at 0° C. for 1 h. Thereaction was quenched with sat. NH₄Cl _((aq)) solution and the aqueousphase was extracted with ether. The organic layer was washed with brine,dried (MgSO₄), filtered and concentrated in vacuo to give a residuewhich was purified by flash column chromatography (1:9 diethylether/pentane) to give 4-cyclopropyl benzaldehyde (1.10 g, 94%) as acolorless oil. ¹H NMR (CDCl₃, 300 MHz): δ 9.94 (s, 1H), 7.76 (d, J=8.5Hz, 2H), 7.19 (d, J=8.5 Hz, 2H), 1.97 (m, 1H), 1.13-1.06 (m, 2H),0.84-0.78 (m, 2H).

Example S2-A Preparation of 4-cyclobutyl benzaldehyde a) Preparation of1-(4-bromophenyl)-cyclobutanol

To a solution of 1,4-dibromobenzene (1.00 g, 4.24 mmol) at −78° C. inether (20 ml) was added n-BuLi (2.65 ml, 1.6 M solution in hexane, 4.24mmol) and the reaction mixture was stirred at −78° C. for 30 min.Cyclobutanone (348 μl, 4.66 mmol) was then added and the reactionmixture was stirred at −78° C. for 15 min. The reaction mixture was thenslowly (over 2 h) warmed to 0° C. and stirred for a further 1 h. Waterwas added followed by sat. NH₄Cl and the reaction mixture was extractedwith ether. The organic layer was washed with brine, dried (MgSO₄),filtered and concentrated in vacuo to give a residue which was purifiedby flash column chromatography (1:4 ether/pentane) to give1-(4-bromophenyl)-cyclobutanol (330 mg, 34%) as a colorless oil. ¹H NMR(CDCl₃, 300 MHz): δ 7.50 (d, J=8.5 Hz, 2H), 7.38 (d, J=8.5 Hz, 2H),2.57-2.48 (m, 2H), 2.41-2.31 (m, 2H), 2.02 (m, 1H), 1.69 (m, 1H).

b) Preparation of 1-bromo-4-cyclobutyl-benzene

To a solution of 1.37 g of 1-(4-bromophenyl)-cyclobutanol (6 mmol) in 15ml DCM were added 1.15 ml of triethylsilane (7.2 mmol) and the mixturewas cooled to −78° C. Then 1.15 ml of boron trifluoride diethyl etheratecomplex were added and the reaction mixture was warmed to −40° C. andstirred for 8 h. The reaction was then quenched by addition of 10%aqueous KHCO₃ and the mixture was extracted three times with DCM. Thecombined extracts were washed with brine, dried with magnesium sulfateand concentrated. The remaining residue was purified by columnchromatography (silica gel; cyclohexane) to give 0.84 g (66%) of1-bromo-4-cyclobutyl-benzene as a colorless liquid. ^(1H) NMR (CDCl₃,300 MHz): δ 1.85 (m, 1H), 1.92-2.18 (m, 3H), 2.33 (m, 2H), 3.49 (quint,J=8.5 Hz, 1H), 7.08 (d, J=8.5 Hz, 2H), 7.40 (d, J=8.5 Hz, 2H).

c) Preparation of 4-cyclobutyl-benzaldehyde

The title compound was synthesized in analogy to 4-cyclopropylbenzaldehyde (described in example S1-A) using 830 mg of1-bromo-4-cyclobutyl-benzene (3.93 mmol), 2.7 ml of a 1.6 molar solutionof n-BuLi in hexane (4.32 mmol) and 605 μl of DMF (7.86 mmol). Theisolated residue was purified by flash column chromatography (5:95EtOAc/cyclohexane) to give 422 mg of 4-cyclobutyl-benzaldehyde (67%) asa colorless liquid. ^(1H) NMR (CDCl₃, 300 MHz): δ 1.89 (m, 1H),1.97-2.26 (m, 3H), 2.40 (m, 2H), 3.63 (quint, J=8.5 Hz, 1H), 7.36 (d,J=8.0 Hz, 2H), 7.81 (d, J=8.0 Hz, 2H), 9.97 (s, 1H).

Example S3-A Preparation of 4-(1-fluoro-cyclobutyl)-benzaldehyde a)Preparation of 1-bromo-4-(1-fluoro-cyclobutyl)-benzene

To a solution of 5.66 g of 1-(4-bromophenyl)-cyclobutanol (24.92 mmol,described in example S2-A) in 70 ml DCM were added 4.23 g of(diethylamino)sulfur trifluoride (95%, 24.92 mmol) at 0° C. The reactionmixture was stirred at 0° C. for 35 min, then sat. NaHCO₃— solution wasadded and the resulting mixture was extracted with DCM. The combinedorganic extracts were washed with brine, dried (MgSO₄), filtered, andconcentrated in vacuo to give a residue which was purified by flashcolumn chromatography (100% pentane) to give1-bromo-4-(1-fluoro-cyclobutyl)-benzene (3.66 g, 64%) as a colorlessliquid.

b) Preparation of 4-(1-fluoro-cyclobutyl)-benzaldehyde

The title compound was synthesized in analogy to 4-cyclopropylbenzaldehyde (described in example S1-A) using 1.64 g of1-bromo-4-(1-fluoro-cyclobutyl)-benzene (7.16 mmol), 4.92 ml of a 1.6molar solution of n-BuLi in hexane (7.87 mmol) and 1.1 ml of DMF (14.32mmol). 4-(1-Fluoro-cyclobutyl)-benzaldehyde was isolated as crudeproduct as a light yellow liquid (1.23 g, 96%). ^(1H) NMR (CDCl₃, 300MHz): δ 1.84 (m, 1H), 2.15 (m, 1H), 2.49-2.81 (m, 5H), 7.63 (d, J=8 Hz,2H), 7.92 (d, J=8 Hz, 2H), 10.03 (s, 1H).

Example S4-A Preparation of4-(1,2,2,2-tetrafluoro-1-trifluoromethyl-ethyl)-benzaldehyde

A solution of 3.5 g of 4-(heptafluoroisopropyl)-toluene (13.4 mmol) in100 ml tetrachloromethane was heated to reflux. Then 2.63 g ofN-bromosuccinimide (14.8 mmol) and 326 mg of dibenzoyl peroxide (1.34mmol) were added in small portions. After 5 h the mixture was cooled to0° C., filtered and the solvent was evaporated. The remaining residuewas dissolved in 15 ml ethanol and was added to a suspension that hadbeen prepared by addition of 2-nitropropane (1.4 ml, 15.5 mmol) to asolution of 340 mg sodium (14.8 mmol) in ethanol. This mixture wasstirred for 3 days. Then it was filtered, the solvent was removed andthe remaining residue was dissolved in EtOAc and washed with 1 N sodiumhydroxide solution, 1 N HCl solution, saturated NaHCO₃ solution and withbrine. The EtOAc layer was then dried with magnesium sulfate, filteredand concentrated. Purification of the residue (silica gel;c-hexane/EtOAc 10:1) gave 1.1 g (30%) of4-(1,2,2,2-tetrafluoro-1-trifluoromethyl-ethyl)-benzaldehyde as a lightyellow oil. ¹H-NMR (CDCl₃, 300 MHz: δ 7.82 (d, J=8 Hz, 2H), 8.03 (d, J=8Hz, 2H), 10.11 (s, 1H).

Example S5-A Preparation of 4-pentafluoroethyl-benzoic acid a)Preparation of 4-pentafluoroethyl-benzonitrile

A mixture of 4-iodobenzonitrile (10.0 g, 43.7 mmol), sodiumpentafluoroproprionate (15.4 g, 82.9 mmol), and copper(I) iodide (16.6g, 87.3 mmol), DMF (160 mL), and toluene (60 mL) was heated at 160° C.for 16 h, allowing most of the toluene to distil off. After cooling,ethyl acetate (200 mL) was added, and the mixture was filtered throughdiatomaceous earth, and the filtrate was partitioned between ethylacetate/heptane and water. The organic layer was washed with brine,dried (MgSO₄), and evaporated. Chromatography (SiO₂, heptane-ethylacetate gradient) afforded the title compound (5.05 g 52%). Yellow oil,MS (EI) 221.1 (M⁺).

b) Preparation of 4-pentafluoroethyl-benzoic acid

A mixture of 4-pentafluoroethyl-benzonitrile (2.98 g, 13.5 mmol) andpotassium hydroxide (3.03 g, 54.0 mmol) in water (40 mL) and ethanol (20mL) was heated at reflux for 16 h. After cooling, the solution waspartitioned between 1 M aq. hydrochloric acid solution and ethylacetate. The organic layer was washed with brine, dried (MgSO₄), andevaporated. Chromatography (SiO₂, heptane-ethyl acetate gradient)produced the title compound (2.76 g, 85%). White solid, MS (ISP) 238.9(M−H)⁻.

Example S6-A Preparation of 4-trimethylsilanyl-benzaldehyde

Bromo-4-(trimethylsilyl)benzene (1.15 g, 5 mmol) was dissolved in THF(30 ml) and cooled to −78° C. Under argon a 1.6 M solution of n-butyllithium in hexane (3.13 ml, 5 mmol) was added dropwise keeping thetemperature below −70° C. The clear colorless solution was stirred at−78° C. for 15 min and DMF (1.156 ml, 15 mmol) was added quickly. Thereaction temperature increased to −68° C. The reaction was stirred foradditional 15 min at −78° C., quenched with 1N aqueous hydrogen chloridesolution and extracted twice with diethyl ether. The combined organiclayers were washed twice with water and once with saturated aqueoussodium chloride solution, dried over sodium sulfate, filtered and thesolvent was evaporated to leave the product as a colorless oil (920 mg,100%). The product was pure enough to be used directly in the next step.MS (ISP) 179.2 (M+H⁺). ^(1H) NMR (CDCl₃, 300 MHz): δ 10.02 (s, 1H) 7.84(d, 2H), 7.69 (d, 2H), 0.31 (s, 9H).

Example S7-A Preparation of 4-(1,1-dimethylpropyl)-benzaldehyde

The title compound was synthesized in analogy to example S1-A using1-bromo-4-(1,1-dimethylpropyl)-benzene (synthesized in analogy to aprocedure described in J. Chem. Res. Miniprint., 1997, 12, 2701-2733)(250 mg, 1.10 mmol), nBuLi (825 μl, 1.6M solution in hexane, 1.32 mmol)and DMF (427 μl, 5.50 mmol). The isolated residue was purified by flashcolumn chromatography (1:9 ether:pentane) to give4-(1,1-dimethylpropyl)-benzaldehyde (175 mg, 90%) as a colorless oil. ¹HNMR (CDCl₃, 300 MHz): 9.99 (s, 1H), 7.82 (d, J=8.5 Hz, 2H), 7.50 (d,J=8.5 Hz, 2H), 1.69 (q, J=7.5 Hz, 2H), 1.32 (s, 6H), 0.68 (t, J=7.5 Hz,3H).

Primary Amines (Compounds of Formula V) Example S1-B Preparation of2-(3-fluoro-5-trifluoromethyl-phenyl)-ethylamine hydrochloride

5.45 g of (3-fluoro-5-trifluoromethyl-phenyl)-acetonitrile (26.3 mmol)were dissolved in 45 ml THF and cooled down to 0° C. under nitrogen. 138ml borane-tetrahydrofuran complex 1M (138 mmol) were then added dropwiseover 20 min by keeping the temperature between 0-2° C. After additionthe reaction mixture was stirred at RT for additional 45 min, andrefluxed for 17 h. The reaction mixture is then cooled down to 0° C. andtreated between 2 and 5° C. with 33 ml methanol over a period of 45 min.After 1 hour refluxing the reaction mixture is concentrated, the residuedissolved in DCM and the amine extrated twice with 1N aqueous HCl. Thecombined aqueous phases are then treated with concentrated NaOH toadjust the pH to 12, and then extrated twice with DCM. The combinedorganic phases were then washed with water, dried over magnesiumsulfate, filtered and concentrated in vacuo leading to 4.44 g colorlessoil. This was dissolved in 100 ml diethylether, treated with 9 ml 2.6NHCl in diethylether, stirred at RT for additional 30 min, filtered anddried under high vacuo, leading to 4.6 g white solid (72%). MS (ISP)207.1 (M+H)⁺.

Example S2-B Preparation of2-(4-chloro-3-trifluoromethyl-phenyl)-ethylamine hydrochloride a)Preparation of (4-chloro-3-trifluoromethyl-phenyl)-acetonitrile

3.94 g of 4-bromomethyl-1-chloro-2-trifluoromethyl-benzene (14.4 mmol)and 1.06 g sodium cyanide (21.6 mmol) were suspended in 12 ml DMSO underargon and stirring and heated to 50° C. for 1 h. The reaction mixturewas then poured on water/ice and extracted four times with DCM. Thecombined organic phases were washed with water, dried with magnesiumsulfate, filtered and concentrated in vacuo, leading to 3.188 g of(4-chloro-3-trifluoromethyl-phenyl)-acetonitrile as a dark red oil,which was directly used in the next step.

b) Preparation of 2-(4-chloro-3-trifluoromethyl-phenyl)-ethylaminehydrochloride

The title compound was synthesized in analogy to2-(3-fluoro-5-trifluoromethyl-phenyl)-ethylamine hydrochloride(described in example S1-B) from 3.188 g of crude(4-chloro-3-trifluoromethyl-phenyl)-acetonitrile (14.5 mmol) and 76 mlof a 1M borane-THF complex solution in THF (76 mmol). The product wasobtained as a white solid (1.52 g, 40%). MS (ISP) 224.1 (M+H)⁺.

Example S3-B Preparation of 2-(4-chloro-3-fluoro-phenyl)-ethylamine(S3-B1) a) Preparation of 1-chloro-2-fluoro-4-(2-nitro-vinyl)-benzene

4-Chloro-3-fluorobenzaldehyde (13 g, 82 mmol) and ammonium acetate (14.6g, 189 mmol) were dissolved in acetic acid (150 ml) and nitromethane(12.6 ml, 234 mmol) was added. The solution was heated to reflux for 1.5h. After cooling to RT water (120 ml) was added. A solid precipitated.The reaction was extracted three times with methylene chloride. Thecombined organic layers were washed with water and sat. aq. NaClsolution, dried over magnesium sulfate, filtered and the solvent wasremoved in vacuo. The residue was purified by flash columnchromatography (Ethyl acetate/cyclohexane:1/4). The crude product wassuspended in heptane, filtered and dried to yield1-chloro-2-fluoro-4-(2-nitro-vinyl)-benzene (10.9 g, 66%) as a lightyellow solid. ^(1H) NMR (CDCl₃, 300 MHz): δ 7.29 (d, J=7.8 Hz, 1H), 7.33(d, J=9.3 Hz, 1H), 7.50 (t, J=7.5H7, 1H), 7.54 (d, J=13.6 Hz, 1H), 7.92(d, J=13.6 Hz, 1H).

b) Preparation of 2-(4-chloro-3-fluoro-phenyl)-ethylamine

Lithium borohydride (2.16 g, 99 mmol) was suspended in THF (50 ml).Trimethylchlorosilane (21.6 g, 198 mmol) was added dropwise. A solutionof 1-chloro-2-fluoro-4-(2-nitro-vinyl)-benzene (5.0 g, 24.8 mmol) in THF(20 ml) was added dropwise. Strong gas evolution and foam formation wasobserved. The white suspension was stirred at RT for 3 days. CarefullyMeOH (80 ml) was added. The solvents were removed in vacuo and theresidue was purified by flash column chromatography (CH₂Cl₂/MeOH+5% aq.NH₄OH 4:1) to yield 2-(4-chloro-3-fluoro-phenyl)-ethylamine (3.1 g, 73%)as a white solid. MS (ISP) 174.1 (M+H)⁺. ^(1H)NMR (DMSO-d, 300 MHz): δ2.92 (t, J=4.8 Hz, 2H), 3.02 (t, J=6.3 Hz, 2H), 7.15 (dd, J=6.0 and 1.2Hz, 1H), 7.38 (dd, J=1.2 and 7.8 Hz), 7.53 (t, J=6.3 Hz, 1H), 7.93 (br,2H).

Example Name * MS (ISP) S3-B2 2-(3-Chloro-5-fluoro-phenyl)-ethylamineS1-B 174.0 (M + H)⁺ hydrochloride S3-B32-(3-Chloro-4-fluoro-phenyl)-ethylamine S1-B 174.1 (M + H)⁺hydrochloride S3-B4 2-(3-Trifluoromethoxy-phenyl)-ethylamine S1-B 206.2(M + H)⁺ hydrochloride S3-B5 2-(3,5-Dichloro-phenyl)-ethylaminehydrochloride S3-B 190.2 (M + H)⁺ S3-B62-(3-Chloro-5-trifluoromethyl-phenyl)-ethylamine S1-B 222.2 (M + H)⁺hydrochloride S3-B7 2-(4-Fluoro-3-trifluoromethyl-phenyl)-ethylamineS1-B 208.2 (M + H)⁺ hydrochloride S3-B82-(3-Benzyloxy-phenyl)-ethylamine hydrochloride S3-B 228.4 (M + H)⁺S3-B9 3-(3-Trifluoromethyl-phenyl)-propylamine S1-B 204.1 (M + H)⁺hydrochloride S3-B10 3-(3-Chloro-phenyl)-propylamine hydrochloride S1-B170.0 (M + H)⁺ S3-B11 3-(4-Chloro-phenyl)-propylamine hydrochloride S1-B170.0 (M + H)⁺ S3-B12 2-(3-Bromo-4-fluoro-phenyl)-ethylamine S3-B 201.1(M + H)⁺ *: Prepared in analogy to example

Example S4-B Preparation of 2-(3-bromo-4-chlorophenyl)-ethylamine a)Preparation of (3-bromo-4-chlorophenyl)-acetonitrile

The title compound was synthesized in analogy to example S2-B using2-bromo-4-bromomethyl-1-chlorobenzene (prepared in analogy to aprocedure described in J. Med. Chem.; 2003; 46(20), 4232-4235) (570 mg,2.00 mmol) and sodium cyanide (147 mg, 3.00 mmol) to give the desiredproduct as a dark red oil which was reacted on without furtherpurification.

b) Preparation of 2-(3-bromo-4-chlorophenyl)-ethylamine

The title compound was synthesized in analogy to example S1-B usingcrude (3-bromo-4-chlorophenyl)-acetonitrile (475 mg, 2.06 mmol) and 1Mborane-THF complex (4.12 ml, 4.12 mmol). The product was obtained as acolorless oil (300 mg, 62%). MS (ISP) 236.0 (M+H)⁺.

Example S5-B Preparation of 2-(4-chloro-3-ethyl-phenyl)-ethylaminehydrochloride a) Preparation of 4-chloro-3-ethyl-benzaldehyde

To a solution of 4.319 g of 4-bromo-1-chloro-2-ethyl-benzene (20 mmol)in 50 ml diethylether, cooled to 0° C., were added dropwise 12.3 ml of1.6M n-BuLi in hexane. After 30 min. stirring at 0° C. and 2 h at RT, asolution of 2.43 ml DMF (31 mmol) in 10 ml diethylether was addeddropwise (temperature raised from 20 to 28° C.). After 1 h additionalstirring at RT, the reaction mixture was acidified with 2N HCl, dilutedwith 150 ml water and extracted with diethylether. The combined organiclayers were washed with brine, dried over magnesium sulfate, filteredoff and concentrated in vacuo. The residue was purified by flash columnchromatography (heptane/AcOEt: 95/5) to yield 2.1 g of a colorless oil.MS (ISP) 168.1 (M+H)⁺.

b) Preparation of 2-(4-chloro-3-ethyl-phenyl)-ethylamine hydrochloride

The title compound was prepared from 4-chloro-3-ethyl-benzaldehyde inanalogy to example S3-B1 steps a) and b). MS (ISP) 184.1 (M+H)⁺.

Example S6-B Preparation of2-(4-benzyloxy-3-tert-butyl-phenyl)-ethylamine hydrochloride a)1-Benzyloxy-2-tert-butyl-4-methyl-benzene

8 g of 2-tert-Butyl-4-methyl-phenol (49 mmol) and 16.36 g of potassiumcarbonate (58 mmol) were stirred in 120 ml DMF until a suspension wasformed. 6.74 ml of benzylchloride were then added dropwise and thereaction mixture was stirred for 24 h at RT. After two hours heating at60° C., the reaction mixture was cooled to RT, filtered off, dilutedwith ethyl acetate, and washed with water followed by brine. The organicphase was dried over magnesium sulphate, filtered off and concentratedunder vacuo. The residue was purified by flash column chromatography(heptane/AcOEt 98/2) to give 8.647 g of a colorless liquid. MS (ISP)255.3 (M+H)⁺.

b) Preparation of 4-benzyloxy-3-tert-butyl-benzaldehyde

A solution of 6.985 g 1-benzyloxy-2-tert-butyl-4-methyl-benzene (27mmol) and 115 g ammoniumcer (IV)-nitrate in 1000 ml acetic acid (50%v/v) was stirred at 90° C. for one hour. After cooling down to RT, thereaction mixture was extracted with AcOEt/heptane 1:9, dried overmagnesium sulfate, filtered off and concentrated under vacuo. Theresidue was purified by flash column chromatography (heptane/AcOEt 95/5to 90/10) to give 3.48 g of an orange solid. MS (ISP) 269.3 (M+H)⁺.

c) Preparation of 2-(4-benzyloxy-3-tert-butyl-phenyl)-ethylaminehydrochloride

The title compound was prepared from4-benzyloxy-3-tert-butyl-benzaldehyde in analogy to example S3-B1 stepsa) and b). MS (ISP) 284.2 (M+H)⁺.

Secondary Amines (Compounds of Formula III) Example S1-C Preparation of(4-tert-butyl-benzyl)-[2-(3,4-dichloro-phenyl)-ethyl]-amine

0.38 ml of 4-tert-butylbenzaldehyde (2.25 mmol) and 0.227 ml2-(3,4-dichloro-phenyl)-ethylamine (1.5 mmol) were dissolved in 4.5 mlmethanol at RT, and after stirring for 30 min at RT, were refluxed for 2h. After cooling down to RT, 85 mg (2.25 mmol) sodium borohydride wereadded and after stirring for 5 min at RT, the reaction mixture was thenrefluxed for 2 h. After cooling down to RT, the reaction mixture wastreated with 4 drops 1 N HCl and concentrated in vacuo. The residue wasdiluted with water/EtOAc. After separation of the organic phase, theaqueous phase was extracted with EtOAc and the combined organic phaseswere washed with brine, dried with magnesium sulfate, filtered off andconcentrated in vacuo. The residue was purified by column chromatography(40 g silica gel; EtOAc/heptane 1:2) to give 515 mg colorless viscousoil (97%). MS (ISP) 336.2 (M+H)⁺.

Example S2-C Preparation of(4-tert-butyl-benzyl)-[2-(4-fluoro-3-trifluoromethyl-phenyl)-ethyl]-amine

0.62 ml of 4-tert-butylbenzaldehyde (3.69 mmol), 600 mg of2-(4-fluoro-3-trifluoro-methyl-phenyl)-ethylamine hydrochloride (2.46mmol) and 340 mg of potassium carbonate (2.46 mmol) were suspended in 7ml methanol at RT, and after stirring for 30 min at RT, were refluxedfor 2 h. After cooling down to RT, 140 mg (3.69 mmol) of sodiumborohydride were added and after stirring for 5 min at RT, the reactionmixture was then refluxed for 3 h. After cooling down to RT, thereaction mixture was treated with 0.5 ml 1 N HCl and concentrated invacuo. The residue was diluted with water/EtOAc. After separation of theorganic phase, the aqueous phase was extracted with EtOAc and thecombined organic phases were washed with brine, dried with magnesiumsulfate, filtered off and concentrated in vacuo. The residue waspurified by column chromatography (40 g silica gel; EtOAc/heptane 1:4then 1:2) to give 784 mg light yellow oil (90%). MS (ISP) 354.3 (M+H)⁺.

Example S3-C Preparation of(4-cyclopropylbenzyl)-[2-(3,4-dichlorophenyl)-ethyl]-amine

A mixture of 4-cyclopropyl benzaldehyde (219 mg, 1.50 mmol),2-(3,4-dichlorophenyl)-ethylamine (284 mg, 1.50 mmol) and molecularsieves (500 mg, 4 Å) in diethyl ether (5 ml) was stirred at RTovernight. The mixture was filtered through celite® and concentrated invacuo to give the corresponding imine which was dissolved in methanol.Sodium borohydride (85 mg, 2.25 mmol) was added and the reaction mixturewas stirred at RT for 4 h. The reaction mixture was then quenched with0.1N NaOH (aq) and the mixture was diluted with EtOAc and washed withbrine. The organic phase was dried (MgSO₄), filtered and concentrated invacuo to give the desired(4-cyclopropylbenzyl)-[2-(3,4-dichlorophenyl)-ethyl]-amine (317 mg, 75%)without further purification as a colorless oil. MS (ISP) 320.2 (M+H)⁺.

Example S4-C Preparation of(4-tert-butyl-benzyl)-[2-(2-chloro-pyridin-4-yl)-ethyl]-amine a)Preparation of 2-chloro-4-trimethylsilanylethynyl-pyridine

A mixture of 2.5 g of 4-bromo-2-chloropyridine (12.6 mmol), 2.2 ml of(trimethylsilyl)acetylene (15.1 mmol), 153 mg of copper(I)iodide (0.79mmol) and 287 mg of bis(triphenylphosphine)palladium(II)chloride (0.41mmol) in triethylamine (15 ml) was stirred at RT for 1 h. Thetriethylamine was then removed in vacuo, water was added and the mixturewas extracted with diethylether. The combined organic extracts were thenwashed with water and brine, dried (Na₂SO₄), filtered and concentratedin vacuo to give a residue which was purified by column chromatography(heptane/EtOAc 100:0 to 98:2) to give2-chloro-4-trimethylsilanylethynyl-pyridine (2.394 g, 91%) as a lightyellow liquid. MS (ISP) 210.1 (M+H)⁺.

b) Preparation of 2-chloro-4-ethynyl-pyridine

To a solution of 2.389 g of 2-chloro-4-trimethylsilanylethynyl-pyridine(11.39 mmol) in THF (90 ml) were added 11.39 ml of a 1 M TBAF solutionin THF at −78° C. and the reaction mixture was stirred for 45 min at 0°C. Then saturated NH₄Cl solution was added and the THF was removed underreduced pressure. The aqueous mixture was extracted with diethyletherand the combined organic extracts were washed with water and brine,dried (Na₂SO₄), filtered and concentrated in vacuo. The remainingresidue was purified by column chromatography (pentane/diethylether100:0 to 4:1) to give 2-chloro-4-ethynyl-pyridine (1.427 g, 91%) as anoff-white solid. ¹H-NMR (CDCl₃, 300 MHz: δ 3.36 (s, 1H), 7.27 (dd, J=5and 1 Hz, 2H), 7.40 (br s, 1H), 8.37 (d, J=8 Hz, 2H).

c) Preparation of(4-tert-butyl-benzyl)-[2-(2-chloro-pyridin-4-yl)-ethyl]-amine

A mixture of 1.386 g of 2-chloro-4-ethynyl-pyridine (10.07 mmol), 2.65ml of 4-tert-butyl-benzylamine (15.11 mmol), 0.58 ml of acetic acid(10.07 mmol) and 666 mg of sodium cyanoborohydride (95% purity, 10.07mmol) in ethanol (12 ml) were heated to 105° C. in a sealed tube for 2d. The reaction mixture was allowed to cool to RT, diluted with 3N NaOHsolution and extracted with DCM. The combined organic extracts werewashed with saturated NaHCO₃ solution and brine, dried (Na₂SO₄),filtered and concentrated in vacuo. After column chromatography(heptane/EtOAc 100:0 to 0:100) 1.688 g (55%) of the title compound wereisolated as a brown liquid. MS (ISP) 303.2 (M+H)⁺.

Example S5-C Preparation of(4-tert-butylbenzyl)-[2-(4-chloro-3-trifluoromethylpyrazol-1-yl)-ethyl]-amineand(4-tert-butylbenzyl)-[2-(4-chloro-5-trifluoromethylpyrazol-1-yl)-ethyl]-aminea) Preparation of 4-chloro-3-trifluoromethyl-1H-pyrazole

To a solution of 3-trifluoromethyl-1H-pyrazole (500 mg, 3.67 mmol) inglacial acetic acid (5 ml) was added a 10% solution of sodiumhypochlorite in water (2188 μl, 3.67 mmol). The reaction mixture wasstirred at RT overnight and then neutralized with sat. sodium carbonate,and extracted with DCM. The organic layers were combined washed withbrine, dried (MgSO₄), filtered and concentrated in vacuo to give thedesired product (480 mg, 77%) as a white solid which did not requirefurther purification. MS (ISP) 169.0 (M−H)⁻.

b) Preparation of 2-(4-tert-butylbenzylamino)-ethanol

The title compound was synthesized in analogy to example S3-C using4-tert-butylbenzaldehyde (1000 mg, 6.17 mmol), ethanolamine (371 μl,6.17 mmol) and sodium borohydride (350 mg, 9.25 mmol). The desiredproduct (1190 mg, 93%) was isolated without further purification as acolorless oil. MS (ISP) 208.3 (M+H)⁺.

c) Preparation of 3-(4-tert-butylbenzyl)-[1,2,3]oxathiazolidine2,2-dioxide

To a solution of 2-(4-tert-butylbenzylamino)-ethanol (1190 mg, 5.74mmol) and triethylamine (3200 μl, 22.96 mmol) in DCM (15 ml) at −15° C.was added a solution of thionylchloride (544 PI, 7.46 mmol) in DCM (4ml) over 10 min. The reaction mixture was stirred at −10° C. for 30 min,filtered and the filtrate was concentrated in vacuo. The residue waspurified by flash column chromatography to give the desired compound(790 mg, 54%) as a white solid. To a mixture of3-(4-tert-butylbenzyl)-[1,2,3]oxathiazolidine 2-oxide (790 mg, 3.12mmol) in DCM (20 ml), acetonitrile (8 ml) and water (8 ml), at 0° C. wasadded NaIO4 (867 mg, 4.05 mmol) followed by RuO₂ (2 mg). The reactionmixture was stirred at 0° C. for 2 h. Water was added and the phaseswere separated and the aqueous phase was extract with ethyl acetate. Theorganic layers were combined washed with brine, dried (MgSO₄), andconcentrated in vacuo. The residue was then purified by flash columnchromatography to give the desired product (640 mg, 76%) as an off whitesolid. MS (ISP) 287.0 (M+NH₄)⁺.

d) Preparation of(4-tert-butylbenzyl)-[2-(4-chloro-3-trifluoromethylpyrazol-1-yl)-ethyl]-amineand(4-tert-butylbenzyl)-[2-(4-chloro-5-trifluoromethylpyrazol-1-yl)-ethyl]-amine

To a suspension of NaH (67 mg, 1.67 mmol) in THF (10 ml) at 0° C. wasadded a solution of 4-chloro-3-trifluoromethyl-1H-pyrazole (190 mg, 1.11mmol) in THF (5 ml) dropwise. The reaction mixture was stirred at 0° C.for 30 min and then 3-(4-tert-butylbenzyl)-oxathiazolidine 2,2-dioxide(300 mg, 1.11 mmol) was added portion wise. The reaction mixture waswarmed to RT and stirred for a further 3 h after which the reactionmixture was quenched with 5 ml 20% (v/v) H₂SO₄. The reaction mixture waswarmed to 60° C. overnight and then cooled to RT and poured into water.The aqueous phase was made basic with 1N NaOH and then extracted withethyl acetate. The organic layers were combined, washed with brine,dried over MgSO₄, filtered and concentrated in vacuo to give a 4:1mixture of regioisomers(4-tert-butylbenzyl)-[2-(4-chloro-3-trifluoromethylpyrazol-1-yl)-ethyl]-amine(210 mg, 52%) MS (ISP) 360.1 (M+H)⁺ and(4-tert-butylbenzyl)-[2-(4-chloro-5-trifluoromethylpyrazol-1-yl)-ethyl]-amine(50 mg, 13%) MS (ISP) 360.1 (M+H)⁺ respectively which were separated byflash column chromatography.

Example S6-C Preparation of(4-tert-butylbenzyl)-[2-(3-cyclopropylphenyl)-ethyl]-amine

To a solution of m-bromophenylcyclopropane (synthesized as described inJ. Org. Chem. 1976, 41, 2262-2266) (100 mg, 0.51 mmol) in dry THF (3 ml)at −78° C. was added nBuLi (317 μl, 1.6M solution in hexane, 0.51 mmol)dropwise. The reaction mixture was stirred at −78° C. for 10 min andthen a solution of 3-(4-tert-butylbenzyl)-[1,2,3]oxathiazolidine2,2-dioxide (109 mg, 0.41 mmol) in THF (1 ml) was added dropwise. Thereaction mixture was warmed to 0° C. over 3 hours and then quenched with5 ml 20% (v/v) H₂SO₄. The reaction mixture was warmed to 60° C.overnight and then cooled to RT and poured into water. The aqueous phasewas made basic with 1N NaOH and then extracted with ethyl acetate. Theorganic layers were combined, washed with brine, dried over MgSO₄,filtered and concentrated in vacuo to give a crude residue which waspurified by flash column chromatography to give(4-tert-butylbenzyl)-[2-(3-cyclopropylphenyl)-ethyl]-amine (72 mg, 58%)as a colorless oil. MS (ISP) 308.4 (M+H)⁺.

Example S7-C Preparation of(4-tert-butylbenzyl)-[2-(3-chloro-5-cyclopropylphenyl)-ethyl]-amine a)Preparation of 1-bromo-3-chloro-5-cyclopropylbenzene

To a solution of 1,3-dibromo-5-chlorobenzene (500 mg, 1.85 mmol) in THF(1 ml) was added cyclopropylmagnesium bromide (3698 μl, 0.5M solution inTHF, 1.85 mmol) in a sealed tube and the reaction mixture was degassedwith argon for 5 min before tetrakis(triphenylphosphine)palladium (0)(107 mg, 0.09 mmol) was added. The resulting solution was heated to 70°C. overnight, cooled to RT and then quenched with sat. NH₄Cl solutionand extracted with pentane. The organic phases were combined, washedwith water and brine, dried over MgSO₄ and filtered through a short padof silica gel to give the desired product (272 mg, 64%) which did notrequire further purification. ^(1H) NMR (CDCl₃, 300 MHz): 7.28 (aptt,J=2.0 Hz, 1H), 7.08 (aptt, J=1.5 Hz, 1H), 6.97 (aptt, J=1.5 Hz, 1H),1.83 (m, 1H), 1.04-0.97 (m, 2H), 0.72-0.67 (m, 2H).

b) Preparation of(4-tert-butylbenzyl)-[2-(3-chloro-5-cyclopropylphenyl)-ethyl]-amine

The title compound was synthesized in analogy to example S6-C using1-bromo-3-chloro-5-cyclopropylbenzene (96 mg, 0.71 mmol) and3-(4-tert-butylbenzyl)-[1,2,3]oxathiazolidine 2,2-dioxide (36 mg, 0.89mmol). The residue was purified by flash column chromatography to givethe desired product (155 mg, 39%) as a colorless oil. MS (ISP) 342.2(M+H)⁺.

Example S8-C Preparation of(4-tert-butylbenzyl)-[2-(3-cyclopropyl-4-fluorophenyl)-ethyl]-amine a)Preparation of 3-cyclopropyl-4-fluorophenylamine

To a solution of 3-bromo-4-fluorophenylamine (synthesized as describedin J. Org. Chem. 1981, 46, 2280-2286) (415 mg, 2.18 mmol), cyclopropylboronic acid (244 mg, 2.84 mmol), potassium phosphate (1.62 g, 7.64mmol), and tricyclohexyl phosphine (61 mg, 0.22 mmol) in toluene (10 ml)and water (0.5 ml) was added palladium acetate (25 mg, 0.11 mmol) andthe reaction mixture was heated to 100° C. overnight. The mixture wasthen cooled to RT and diluted with water and extracted with ether. Theorganic phases were combined, washed with brine, dried (MgSO₄), filteredand concentrated in vacuo to give a residue which was purified by flashcolumn chromatography to give 3-cyclopropyl-4-fluorophenylamine (210 mg,64%). MS (ISP) 152.2 (M+H)⁺.

b) Preparation of 2-cyclopropyl-1-fluoro-4-iodobenzene

To a solution of 3-cyclopropyl-4-fluorophenylamine (210 mg, 1.39 mmol)in DME (1.5 ml) was added caesium iodide (360 mg, 1.39 mmol), cuprousiodide (82 mg, 0.43 mmol), iodine (176 mg, 0.70 mmol) and isoamylnitrite (1.11 ml, 8.34 mmol). The reaction mixture was heated to 60° C.for 2 h. The reaction mixture was cooled to RT and partitioned betweenpentane and sat. NH₄Cl solution. The organic layer was separated, washedwith 5% sodium thiosulfite and brine, dried (MgSO₄), filtered andconcentrated in vacuo to give a residue which was purified by flashcolumn chromatography (100% pentane) to yield the desired2-cyclopropyl-1-fluoro-4-iodobenzene (262 mg, 72%) as a colorless oil.^(1H) NMR (CDCl₃, 300 MHz): 7.40 (m, 1H), 7.17 (m, 1H), 6.76 (m, 1H),2.02 (m, 1H), 1.03-0.96 (m, 2H), 0.74-0.68 (m, 2H).

c) Preparation of(4-tert-butylbenzyl)-[2-(3-cyclopropyl-4-fluorophenyl)-ethyl]-amine

The title compound was synthesized in analogy to example S6-C using2-cyclopropyl-1-fluoro-4-iodobenzene (100 mg, 0.38 mmol) and3-(4-tert-butylbenzyl)-[1,2,3]oxathiazolidine 2,2-dioxide (103 mg, 0.38mmol). The residue was purified by flash column chromatography to givethe desired product (35 mg, 28%) as a colorless oil. MS (ISP) 326.3(M+H)⁺.

Example S9-C Preparation of[2-(4-fluoro-phenyl)-ethyl]-(4-pentafluoroethyl-benzyl)-amine (S9-C1) a)Preparation ofN-[2-(4-fluoro-phenyl)-ethyl]-4-pentafluoroethyl-benzamide

A solution of 4-pentafluoroethyl-benzoic acid (500 mg, 2.08 mmol),2-(4-fluorophenyl)ethylamine (319 mg, 2.29 mmol), 4-methylmorpholine(632 mg, 6.24 mmol), and HBTU (1.19 g, 3.12 mmol) in DMF (38 mL) wasstirred at RT for 16 h, then the reaction mixture was partitionedbetween water and ethyl acetate. The organic layer was washed withbrine, dried (MgSO₄), and evaporated. Chromatography (SiO₂,heptane-ethyl acetate gradient) afforded the title compound (746 mg,99%). White solid, MS (ISP) 362.2 (M+H)⁺.

b) Preparation of[2-(4-fluoro-phenyl)-ethyl]-(4-pentafluoroethyl-benzyl)-amine

Borane-tetrahydrofuran complex solution (1 M in THF, 6.5 mL, 6.5 mmol)was added at 0° C. to a solution ofN-[2-(4-fluoro-phenyl)-ethyl]-4-pentafluoroethyl-benzamide (740 mg, 2.04mmol) in THF (8 mL), and the homogeneous solution was heated at refluxover 3 h. After cooling, excess reagent was destroyed by carefuladdition of methanol at 0° C. Volatile material was removed bydistillation, then the residue was dissolved in 5% ethanolic sulfuricacid solution (5 mL). The solution was refluxed for 90 min, thenpartitioned between 2 M aq. sodium hydroxide solution and ethyl acetate.The organic layer was washed with brine, dried (MgSO₄), and evaporated.Chromatography (SiO₂, DCM/methanol/NH₄OH 95:5:0.1) afforded the titlecompound (652 mg, 92%). Colorless oil, MS (ISP) 348.2 (M+H)⁺.

Example Name * MS (ISP) S9-C2(4-tert-Butyl-benzyl)-[2-(3-trifluoromethyl- S1-C 336.3 (M + H)⁺phenyl)-ethyl]-amine S9-C3 (4-tert-Butyl-benzyl)-phenethyl-amine S1-C268.3 (M + H)⁺ S9-C4 (4-tert-Butyl-benzyl)-[2-(3-trifluoromethoxy- S2-C352.3 (M + H)⁺ phenyl)-ethyl]-amine S9-C5(4-tert-Butyl-benzyl)-[2-(4-chloro-3- S2-C 370.2 (M + H)⁺trifluoromethyl-phenyl)-ethyl]-amine S9-C6 (4-Cyclobutlylbenzyl)-[2-(3-S2-C 350.3 (M + H)⁺ trifluoromethoxyphenyl)-ethyl]-amine S9-C7Butyl-(4-tert-butyl-benzyl)-amine S1-C 220.4 (M + H)⁺ S9-C8(4-tert-Butyl-benzyl)-[2-(3-chloro-4-fluoro- S2-C 320.3 (M + H)⁺phenyl)-ethyl]-amine S9-C9[2-(4-Chloro-phenyl)-ethyl]-[4-(1,2,2,2-tetrafluoro- S1-C 414.3 (M + H)⁺1-trifluoromethyl-ethyl)-benzyl]-amine S9-C10(4-Cyclobutyl-benzyl)-[2-(3-trifluoromethyl- S1-C 334.4 (M + H)⁺phenyl)-ethyl]-amine S9-C11(4-Cyclobutyl-benzyl)-[2-(4-fluoro-phenyl)-ethyl]- S1-C 284.4 (M + H)⁺amine S9-C12 [2-(4-Chloro-phenyl)-ethyl]-(4-cyclobutyl-benzyl)- S1-C300.4 (M + H)⁺ amine S9-C13(4-tert-Butyl-benzyl)-[2-(4-fluoro-phenyl)-ethyl]- S1-C 286.2 (M + H)⁺amine S9-C14 (4-tert-Butyl-benzyl)-[2-(4-chloro-phenyl)-ethyl]- S1-C302.3 (M + H)⁺ amine S9-C15(4-tert-Butyl-benzyl)-[2-(3-chloro-phenyl)-ethyl]- S1-C 302.3 (M + H)⁺amine S9-C16 [4-(1-Fluoro-cyclobutyl)-benzyl]-[2-(3- S1-C 352.4 (M + H)⁺trifluoromethyl-phenyl)-ethyl]-amine S9-C17[2-(3,4-Dichloro-phenyl)-ethyl]-[4-(1-fluoro- S1-C 352.3 (M + H)⁺cyclobutyl)-benzyl]-amine S9-C18(4-tert-Butyl-benzyl)-[2-(6-trifluoromethyl- S4-C 337.3 (M + H)⁺pyridin-2-yl)-ethyl]-amine S9-C19[2-(4-Chloro-phenyl)-ethyl]-(4-trifluoromethoxy- S1-C 330.2 (M + H)⁺benzyl)-amine S9-C20 [2-(4-Chloro-phenyl)-ethyl]-(4-trifluoromethyl-S1-C 313.9 (M + H)⁺ benzyl)-amine S9-C21[2-(3-Trifluoromethyl-phenyl)-ethyl]-(4- S1-C 352.4 (M + H)⁺trimethylsilanyl-benzyl)-amine S9-C22[2-(4-Chloro-phenyl)-ethyl]-(4-trimethylsilanyl- S1-C 318.1 (M + H)⁺benzyl)-amine S9-C23 [2-(4-Fluoro-phenyl)-ethyl]-(4-trimethylsilanyl-S1-C 302.2 (M + H)⁺ benzyl)-amine S9-C24[2-(3,4-Dichloro-phenyl)-ethyl]-(4- S1-C 352.2 (M + H)⁺trimethylsilanyl-benzyl)-amine S9-C25(4-tert-Butyl-benzyl)-[2-(4-chloro-3-fluoro- S1-C 320.3 (M + H)⁺phenyl)-ethyl]-amine S9-C26 [2-(3-Trifluoromethoxy-phenyl)-ethyl]-(4-S1-C 368.2 (M + H)⁺ trimethylsilanyl-benzyl)-amine S9-C27[2-(4-Chloro-phenyl)-ethyl]-[4-(1-fluoro- S3-C 318.1 (M + H)⁺cyclobutyl)-benzyl]-amine S9-C28[4-(1-Fluoro-cyclobutyl)-benzyl]-[2-(4-fluoro- S3-C 302.3 (M + H)⁺phenyl)-ethyl]-amine S9-C29 [2-(3-Chloro-phenyl)-ethyl]-[4-(1-fluoro-S3-C 318.1 (M + H)⁺ cyclobutyl)-benzyl]-amine S9-C30[2-(4-Chloro-phenyl)-ethyl]-[4-(1,1-dimethyl- S1-C 316.1 (M + H)⁺propyl)-benzyl]-amine S9-C31 [4-(1,1-Dimethyl-propyl)-benzyl]-[2-(3-S3-C 350.3 (M + H)⁺ trifluoromethyl-phenyl)-ethyl]-amine S9-C32(4-tert-Butyl-benzyl)-(3-phenyl-propyl)-amine S1-C 282.3 (M + H)⁺ S9-C33(4-tert-Butyl-benzyl)-[2-(3-cyclopropyl-5-fluoro- S7-C 326.2 (M + H)⁺phenyl)-ethyl]-amine S9-C34 (4-tert-Butyl-benzyl)-[2-(3-chloro-5-fluoro-S2-C 320.1 (M + H)⁺ phenyl)-ethyl]-amine S9-C35(4-tert-Butyl-benzyl)-[2-(3-chloro-5- S2-C 370.0 (M + H)⁺trifluoromethyl-phenyl)-ethyl]-amine S9-C36(4-tert-Butyl-benzyl)-[2-(3-fluoro-5- S2-C 354.3 (M + H)⁺trifluoromethyl-phenyl)-ethyl]-amine S9-C37[2-(3,5-Bis-trifluoromethyl-phenyl)-ethyl]-(4-tert- S1-C 404.5 (M + H)⁺butyl-benzyl)-amine S9-C38(4-tert-Butyl-benzyl)-[2-(3,5-dichloro-phenyl)- S1-C 336.0 (M + H)⁺ethyl]-amine S9-C39 (4-tert-Butyl-benzyl)-(2-p-tolyl-ethyl)-amine S1-C282.2 (M + H)⁺ S9-C40 (4-tert-Butyl-benzyl)-[2-(4-trifluoromethyl- S1-C336.2 (M + H)⁺ phenyl)-ethyl]-amine S9-C41[2-(3-Bromo-phenyl)-ethyl]-(4-tert-butyl-benzyl)- S1-C 346.1 (M + H)⁺amine S9-C42 [2-(3-Bromo-4-chlorophenyl)-ethyl]-(4-tert- S3-C 382.3 (M +H)⁺ butylbenzyl)-amine S9-C43[2-(3-Benzyloxy-phenyl)-ethyl]-(4-tert-butyl- S2-C 374.3 (M + H)⁺benzyl)-amine S9-C44 (4-tert-Butyl-benzyl)-[3-(3-trifluoromethyl- S2-C350.4 (M + H)⁺ phenyl)-propyl]-amine S9-C45(4-tert-Butyl-benzyl)-[2-(4-chloro-3-ethyl-phenyl)- S1-C 330.4 (M + H)⁺ethyl]-amine S9-C46 (4-tert-Butyl-benzyl)-[3-(3-chloro-phenyl)-propyl]-S2-C 316.1 (M + H)⁺ amine S9-C47(4-tert-Butyl-benzyl)-[3-(4-chloro-phenyl)-propyl]- S2-C 316.1 (M + H)⁺amine S9-C48 [2-(4-Benzyloxy-3-tert-butyl-phenyl)-ethyl]-(4-tert- S2-C430.5 (M + H)⁺ butyl-benzyl)-amine S9-C49[2-(3-Bromo-4-fluoro-phenyl)-ethyl]-(4-tert-butyl- S1-C 366.1 (M + H)⁺benzyl)-amine *: Prepared in analogy to example

Example S10-C Preparation of(4-tert-butyl-benzyl)-[2-(3-ethyl-phenyl)-ethyl]-amine a) Preparation of[2-(3-bromo-phenyl)-ethyl]-(4-tert-butyl-benzyl)-carbamic acidtert-butyl ester

To a solution of [2-(3-bromo-phenyl)-ethyl]-(4-tert-butyl-benzyl)-amine(3544 mg, 10.23 mmol) in DCM (30 ml) was added di-tert-butyl-dicarbonate(2507 mg, 11.3 mmol) at 0° C. The reaction mixture was stirred for 30min at 0° C. and then at RT over night. Saturated NH₄Cl solution wasadded and the mixture was extracted with DCM. The combined organicextracts were washed with 10% KHCO₃ solution and brine and were dried(Na₂SO₄). After evaporation of the solvent the crude title compound(4722 mg) was obtained as a colorless oil. MS (ISP) 446.4 (M+H)⁺.

b) Preparation of(4-tert-butyl-benzyl)-[2-(3-trimethylsilanylethynyl-phenyl)-ethyl]-carbamicacid tert-butyl ester

A mixture of the crude[2-(3-bromo-phenyl)-ethyl]-(4-tert-butyl-benzyl)-carbamic acidtert-butyl ester (515 mg, 1.154 mmol),bis(triphenylphosphine)palladium(II)chloride (32 mg, 0.0461 mmol), CuI(11 mg, 0.0577 mmol) and (trimethylsilyl)acetylene (251 μl, 1.73 mmol)in triethylamine (3.4 ml) was heated in a sealed tube at 105° C. overnight. The mixture was then cooled to RT, diluted with sat.NaHCO₃-solution and extracted three times with ethyl acetate. Thecombined ethyl acetate layers were then washed with water and brine andwere dried (Na₂SO₄) and evaporated. The remaining residue was purifiedby chromatography (heptane/EtOAc 100:0 to 95:5) to obtain the titlecompound as a yellow gum (441 mg, 82%). MS (ISP) 464.4 (M+H)⁺.

c) Preparation of(4-tert-butyl-benzyl)-[2-(3-ethynyl-phenyl)-ethyl]-carbamic acidtert-butyl ester

To a solution of(4-tert-butyl-benzyl)-[2-(3-trimethylsilanylethynyl-phenyl)-ethyl]-carbamicacid tert-butyl ester (440 mg, 0.949 mmol) in THF (7.6 ml) was added a 1molar solution of TBAF in THF (949 μl, 0.949 mmol) at −78° C. After 15min at −78° C. the solution was allowed to warm to 0° C. for 30 min.Then brine was added and the mixture was extracted with ether. Thecombined ether layers were dried (Na₂SO₄) and evaporated and theremaining residue was purified by chromatography (pentane/ether 100:0 to90:10) to obtain the title compound as a colorless oil (314 mg, 84%). MS(ISP) 392.3 (M+H)⁺.

d) Preparation of(4-tert-butyl-benzyl)-[2-(3-ethyl-phenyl)-ethyl]-carbamic acidtert-butyl ester

A solution of(4-tert-butyl-benzyl)-[2-(3-ethynyl-phenyl)-ethyl]-carbamic acidtert-butyl ester (149 mg, 0.381 mmol) in methanol (12 ml) was stirred atRT under an atmosphere of hydrogen in the presence of a catalytic amountof palladium on charcoal (5%) for 2 days. The reaction mixture was thenfiltered and evaporated and the remaining residue was purified bychromatography (heptane/EtOAc 100:0 to 95:5) to obtain the titlecompound as a colorless oil (73 mg, 48%). MS (ISP) 396.4 (M+H)⁺.

e) Preparation of (4-tert-butyl-benzyl)-[2-(3-ethyl-phenyl)-ethyl]-amine

To a solution of(4-tert-butyl-benzyl)-[2-(3-ethyl-phenyl)-ethyl]-carbamic acidtert-butyl ester 66 mg, 0.166 mmol) in DCM (1 ml) was addedtrifluoroacetic acid (128 μl, 1.668 mmol) at 0° C. The reaction mixturewas allowed to warm to RT and was stirred over night. The mixture wasthen basified with 1 N NaOH and extracted with DCM. The combinedextracts were dried (Na₂SO₄) and evaporated to obtain the title compoundas a colorless gum (45 mg, 92%). MS (ISP) 296.5 (M+H)⁺.

Example S11-C Preparation of(4-tert-butylbenzyl)-[2-(4-chloro-3-cyclopropylphenyl)-ethyl]-amine and(4-tert-butylbenzyl)-[2-(3,4-dicyclopropylphenyl)-ethyl]-amine

The title compounds were synthesized in analogy to3-cyclopropyl-4-fluorophenylamine (step a, example S8-C) using[2-(3-bromo-4-chlorophenyl)-ethyl]-(4-tert-butylbenzyl)-amine (128 mg,0.34 mmol) and cyclopropyl boronic acid (72 mg, 0.84 mmol). The residuewas purified by flash column chromatography to give an unseperable 1:4mixture of products(4-tert-butylbenzyl)-[2-(4-chloro-3-cyclopropylphenyl)-ethyl]-amine (13mg, 11%), MS (ISP) 342.2 (M+H)⁺ and(4-tert-butylbenzyl)-[2-(3,4-dicyclopropylphenyl)-ethyl]-amine (55 mg,47%), MS (ISP) 348.4 (M+H)⁺ which was reacted on without furtherpurification.

Example S12-C Preparation of(4-tert-butylbenzyl)-[2-(4-chloro-3-isopropylphenyl)-ethyl]-amine a)Preparation of 2-(5-bromo-2-chlorophenyl)-propan-2-ol

To a solution of 5-bromo-2-chlorobenzoic acid methyl ester (1 g, 4 mmol,1 eq) in THF (20 ml) at −78° C. was added a 3M solution of methylmagnesium bromide (4 ml, 12 mmol, 3 eq) in THF dropwise. The reactionmixture was then warmed to RT and stirred overnight. The mixture waspoured into sat. ammonium chloride solution and extracted with ether.The organic layers were combined, washed with brine, dried (MgSO₄),filtered and concentrated in vacuo to give a residue which was purifiedby flash column chromatography (0 to 20% ether in pentane) to give thedesired product as a colorless oil (980 mg, 98%).

b) Preparation of 4-bromo-1-chloro-2-isopropenylbenzene

To a solution of 2-(5-bromo-2-chlorophenyl)-propan-2-ol (500 mg, 2 mmol,1 eq) in toluene (5 ml) was added a catalytic amount ofp-toluenesulfonic acid (38 mg, 0.2 mmol, 0.1 eq) and the solution wasrefluxed under a Dean-Stark H₂O separator overnight. The reactionmixture was allowed to cool to RT and was diluted with ether. Themixture was washed with sat. NaHCO₃-solution and brine, dried (MgSO₄),filtered and concentrated in vacuo to give the desired product (357 mg,77%) as a colorless oil which did not require further purification.

c) Preparation of 4-bromo-1-chloro-2-isopropylbenzene

A mixture of 4-bromo-1-chloro-2-isopropenylbenzene (357 mg, 1.54 mmol, 1eq) and PtO₂ (35 mg, 0.15 mmol, 0.1 eq) in 4 ml toluene was stirredunder an atmosphere of hydrogen at RT overnight. The reaction mixturewas then filtered through celite® and the filtrate was evaporated todryness to give the desired product (260 mg, 72%). ^(1H) NMR (CDCl₃, 300MHz): 7.39 (d, J=2 Hz, 1H), 7.26-7.16 (m, 2H), 3.35 (sept, J=7 Hz, 1H),1.23 (d, J=7 Hz, 6H).

d) Preparation of(4-tert-butylbenzyl)-[2-(4-chloro-3-isopropylphenyl)-ethyl]-amine

The title compound was synthesized in analogy to example S6-C using4-bromo-1-chloro-2-isopropylbenzene (120 mg, 0.51 mmol), and3-(4-tert-butylbenzyl)-[1,2,3]oxathiazolidine 2,2-dioxide (138 mg, 0.51mmol). The residue was purified by flash column chromatography to givethe desired product (74 mg, 42%) as a light yellow oil. MS (ISP) 344.3(M+H)⁺.

Acids (Compounds of Formula II) Example S1-D Preparation of2-chloro-6-trifluoromethyl-isonicotinic acid a) Preparation of6-chloro-3-iodo-2-trifluoromethyl-pyridine

To a stirred solution of 7.1 ml of n-BuLi (1.6M in hexane, 11.3 mmol) in7 ml THF under argon at −73° C. were added 1.6 ml of diisopropylamine(11.3 mmol) in 3 ml THF within 8 min. After 10 min stirring at the sametemperature a solution of 1 g of 2-chloro-6-(trifluoromethyl)-pyridine(5.51 mmol) in 5 ml THF was added within 15 min (temperature between −76and −75° C.). The dark brown solution was stirred at −75° C. for 1 h 15min. Finally a solution of 1.4 g of iodine (5.51 mmol) in 10 ml THF wasadded at −75° C. over 25 min. After additional 45 min stirring at thesame temperature 12 ml 2M aqueous HCl were added within 2 min(temperature raised from −78 to −50° C. The cooling device was thenremoved, the reaction mixture diluted with diethylether. Afterseparation of the organic phase, the aqueous phase was reextracted withdiethylether. The combined organic phases were successively washed with10 ml 1M sodium thiosulfate, saturated NaHCO₃ and brine, dried overmagnesium sulfate, filtered off and concentrated in vacuo to yield 1.54(69%) of 6-chloro-3-iodo-2-trifluoromethyl-pyridine as a brown semisolidresidue. MS: 307.0

b) Preparation of 2-chloro-4-iodo-6-trifluoromethyl-pyridine

To a stirred solution of 3.05 ml of n-BuLi (1.6 M in hexane, 4.88 mmol)under argon at −75° C. was added 0.69 ml of diisopropylamine (4.88 mmol)in 2.5 ml THF over 5 min (temperature between −72 and −75° C.). After 10min at −75° C. a solution of 1.5 g of6-chloro-3-iodo-2-trifluoromethyl-pyridine (4.88 mmol) in 3.5 ml THF wasadded dropwise over 20 min at the same temperature. After 1.5 hoursstirring at −75° C., 6 ml 2M aqueous HCl were added (temperature wasallowed to raise to RT). The mixture was then diluted with water,extracted with diethylether and the combined organic phases weresuccessively washed with saturated NaHCO₃ solution and brine, dried overmagnesium sulfate, filtered off and concentrated in vacuo. The residuewas purified by silicagel chromatography (eluent:heptane/AcOEt 95:5)leading to 1.145 g (69%) of 2-chloro-4-iodo-6-trifluoromethyl-pyridineas a white powder. MS: 307.0

c) Preparation of 2-chloro-6-trifluoromethyl-isonicotinic acid

To a stirred solution of 1.1 g of2-chloro-4-iodo-6-trifluoromethyl-pyridine (3.58 mmol) in 15 ml THFunder argon at −75° C., were added 2.2 ml of n-BuLi (1.6 M in hexane)within 15 min (temperature kept between −72° C. and −75° C.). After 5additional min stirring at −75° C., the reaction mixture was poured onan excess of freshly crushed dry ice and stirred until RT was reached.The reaction mixture was then concentrated in vacuo, the remainingresidue treated with 2M aqueous HCl and the resulting mixture wasextrated with diethylether. The combined organic phases were washed withwater, and then extracted with saturated NaHCO₃ solution. The aqueousphase was then acidified with concentrated HCl, extracted twice withdiethylether and the combined organic phases were washed with brine,dried over magnesium sulfate, filtered and concentrated in vacuo. Theremaining residue was recrystalized from 12 ml hot n-hexane, leading to0.459 g (56%) of 2-chloro-6-trifluoromethyl-isonicotinic acid as anoff-white solid. MS: 224.0 (M−H)⁻.

Example S2-D Preparation of 3-chloro-4-fluoro-5-trifluoromethyl-benzoicacid

To a stirred solution of 2.03 ml of sec-BuLi (1.3M in cyclohexane, 2.64mmol) and 0.4 ml of TMEDA under argon at −90° C. was added a solution of0.25 g of 4-fluoro-3-trifluoromethyl-benzoic acid (1.2 mmol) in 8 ml THFover 20 min (temperature kept between −92° C. and −88° C.). After 30 minstirring at the same temperature, the initially light orange suspensionturned brown. A solution of 1.14 g of hexachloroethane (4.82 mmol) in 10ml THF was then added within 2 min (temperature raised to −62° C.). Thereaction mixture was then left to warm slowly to RT (1 hour) and treatedcarefully with 2 ml water. The reaction mixture was then concentrated invacuo, diluted with water and extracted with diethylether. The aqueousphase was then acidified with concentrated HCl and extrated twice withethylacetate. The combined ethylacetate phases were subsequently washedwith water (3×) and brine (1×), dried over magnesium sulfate, filteredand concentrated in vacuo to yield 0.28 g of a residue which waspurified by silicagel chromatography (eluent heptane/AcOEt 90:10 to75:25) to yield 22 mg of 3-chloro-4-fluoro-5-trifluoromethyl-benzoicacid as a light yellow solid. MS: 241.1 (M−H)⁻.

Example S3-D Preparation of 3-chloro-5-cyclopropylbenzoic acid

To a solution of 1-bromo-3-chloro-5-cyclopropylbenzene (300 mg, 1.30mmol) at −78° C. in THF (5 ml) was added nBuLi (890 μl, 1.6M solution inhexane, 1.43 mmol) dropwise. The resulting solution was stirred at −78°C. for 10 min after which solid carbon dioxide was added and thereaction mixture was warmed to RT over 3 hours. The reaction mixture wasquenched with water and then extracted with ether. The aqueous phase wasthen made acidic with 1N HCl and then extracted with ethyl acetate. Theorganic phases were combined, washed with brine, dried (MgSO₄), filteredand concentrated in vacuo to give the desired product3-chloro-5-cyclopropylbenzoic acid (178 mg, 70%) which did not requirefurther purification. MS (ISP) 195.1 (M−H)⁻.

Example S4-D Preparation of6-chloro-4-trifluoromethyl-pyridine-2-carboxylic acid

To a solution of 300 mg of2-chloro-6-methyl-4-(trifluoromethyl)-pyridine (1.49 mmol) in pyridine(5 ml) was added a solution of 1.61 g of tetrabutylammonium permanganate(4.46 mmol) in pyridine (4.5 ml) and the reaction mixture was stirred at80° C. for 3 h. The reaction mixture was then poured into a mixture ofwater and ice and then NaHSO₃ solution (40% in water) was added untilthe color turned light yellow. The mixture was then acidified byaddition of 2N HCl and extracted with ethyl acetate. The combinedorganic layers were then washed with 1N HCl and brine, dried (Na₂SO₄),filtered and concentrated. The remaining residue was purified bychromatography (DCM/MeOH 100:0 to 90:10) to yield 224 mg (67%) of a grayliquid. MS (ISP) 224.3 (M−H)⁻.

Example S5-D Preparation of6-Methyl-2-trifluoromethyl-pyrimidine-4-carboxylic acid a) Preparationof 6-methyl-2-trifluoromethyl-pyrimidine-4-carboxylic acid ethyl ester

2.241 g (20 mmol) of 2,2,2-trifluoro-acetamidine were dissolved in 80 mlethanol and treated with 3.163 g (20 mmol) of 2,4-dioxo-pentanoic acidethyl ester. The resulting solution was cooled to 0-5° C. and treatedwith 120 ml of HCl-saturated ethanol. The reaction mixture was allowedto warm-up to RT and stirred for additional 3 hours. The mixture wasthen added dropwise under cooling to 800 ml saturated NaHCO₃ solution.The resulting mixture was then extracted twice with 300 ml DCM and thecombined organic phases were dried over magnesium sulfate, filtered andconcentrated in vacuo to yield 3.1 g of a yellow oil. This residue wasthen purified by silicagel chromatography (eluent:heptane/ethyl acetate100:0 to 30:70) leading to a colorless oil which crystallizedspontaneously, leading to 1.3 g of6-methyl-2-trifluoromethyl-pyrimidine-4-carboxylic acid ethyl ester.

b) Preparation of 6-methyl-2-trifluoromethyl-pyrimidine-4-carboxylicacid

1.3 g (5.551 mmol) of 6-methyl-2-trifluoromethyl-pyrimidine-4-carboxylicacid ethyl ester were dissolved in 30 ml dioxane and treated with 11.1ml (11.1 mmol) 1 N NaOH and stirred for 2 hours at RT. The reactionmixture was then treated with 11.1 ml (11.1 mmol) 1 N HCl andconcentrated in vacuo. The resulting solid residue was then suspended inDCM-methanol, filtered-off, washed with additional DCM-methanol and thecombined organic phases were then concentrated in vacuo, to yield 1.1 g(96%) of 6-methyl-2-trifluoromethyl-pyrimidine-4-carboxylic acid. MS:205.1 (M−H)⁻.

Compounds of Formula I EXAMPLE 1 Preparation ofN-(4-tert-butyl-benzyl)-3-chloro-N-[2-(4-chloro-phenyl)-ethyl]-2-fluoro-5-trifluoromethyl-benzamide(B1)

To a solution of 50 mg of 3-chloro-2-fluoro-5-trifluoromethyl-benzoicacid (0.206 mmol) and 68 mg (0.225 mmol) of(4-tert-butylbenzyl)-[2-(4-chlorophenyl)-ethyl]-amine in 3 ml of DMFwere added 117 mg of HBTU (0.31 mmol) and 0.063 ml (0.62 mmol) of4-methylmorpholine. After stirring the reaction mixture over night at RTit was poured on a mixture of 15 ml of brine and 15 ml of water andextracted with ethyl acetate. The combined organic phases were washedwith brine, dried with magnesium sulfate, filtered and concentrated invacuo. The residue was purified by column chromatography (silica gel;heptane/EtOAc 95:5) to give 76 mg (70%) of a light yellow amorphousmaterial. MS (ISP) 526.0 (M+H)⁺. In analogy to example 1:

Example Name MS B2 N-(4-tert-Butyl-benzyl)-N-[2-(3,4-dichloro-phenyl)-459.3 [ISP(M + H)+] ethyl]-2-fluoro-nicotinamide B3N-(4-tert-Butyl-benzyl)-4-chloro-N-[2-(3,4-dichloro- 475.2 [ISP(M + H)+]phenyl)-ethyl]-nicotinamide B4N-(4-tert-Butyl-benzyl)-2,5-dichloro-N-[2-(3,4- 509 [ISP(M + H)+]dichloro-phenyl)-ethyl]-nicotinamide B55-Bromo-N-(4-tert-butyl-benzyl)-2-chloro-N-[2-(3,4- 553 [ISP(M + H)+]dichloro-phenyl)-ethyl]-nicotinamide B6N-(4-tert-Butyl-benzyl)-2-chloro-N-[2-(3,4-dichloro- 493.3 [ISP(M + H)+]phenyl)-ethyl]-5-fluoro-nicotinamide B7N-(4-tert-Butyl-benzyl)-2-chloro-N-[2-(3,4-dichloro- 543.1 [ISP(M + H)+]phenyl)-ethyl]-5-trifluoromethyl-isonicotinamide B8N-(4-tert-Butoxy-benzyl)-3-chloro-2-fluoro-5- 576.1 [ISP(M + H)+]trifluoromethyl-N-[2-(3-trifluoromethyl-phenyl)- ethyl]-benzamide B9N-(4-tert-Butyl-benzyl)-2,6-dichloro-N-[2-(3- 509.3 [ISP(M + H)+]trifluoromethyl-phenyl)-ethyl]-isonicotinamide B10N-(4-tert-Butyl-benzyl)-2,6-dichloro-N-[2-(3-fluoro- 527 [ISP(M + H)+]5-trifluoromethyl-phenyl)-ethyl]-isonicotinamide B11N-(4-tert-Butyl-benzyl)-2,6-dichloro-N-[2-(4-fluoro- 527 [ISP(M + H)+]3-trifluoromethyl-phenyl)-ethyl]-isonicotinamide B12N-(4-tert-Butyl-benzyl)-2-chloro-N-[2-(3-fluoro-5- 561.3 [ISP(M + H)+]trifluoromethyl-phenyl)-ethyl]-6-trifluoromethyl- isonicotinamide B13N-(4-tert-Butyl-benzyl)-2,6-dichloro-N-[2-(3-chloro- 543.1 [ISP(M + H)⁺]5-trifluoromethyl-phenyl)-ethyl]-isonicotinamide B14N-(4-tert-Butyl-benzyl)-2-chloro-N-[2-(3-chloro-5- 577.2 [ISP(M + H)⁺]trifluoromethyl-phenyl)-ethyl]-6-trifluoromethyl- isonicotinamide B15N-(4-tert-Butyl-benzyl)-2-chloro-6-trifluoromethyl- 543.1 [ISP(M + H)⁺]N-[2-(3-trifluoromethyl-phenyl)-ethyl]- isonicotinamide B16N-(4-tert-Butyl-benzyl)-2-chloro-N-[2-(4-fluoro-3- 561.3 [ISP(M + H)⁺]trifluoromethyl-phenyl)-ethyl]-6-trifluoromethyl- isonicotinamide B17N-(4-tert-Butyl-benzyl)-2,6-dichloro-N-[2-(4-chloro- 493.1 [ISP(M + H)⁺]3-fluoro-phenyl)-ethyl]-isonicotinamide B18N-(4-tert-Butyl-benzyl)-2-chloro-N-[2-(3,4-dichloro- 543.2 [ISP(M + H)⁺]phenyl)-ethyl]-6-trifluoromethyl-isonicotinamide B19N-(4-tert-Butyl-benzyl)-3-chloro-N-[2-(2-chloro- 509.4 [ISP(M + H)⁺]pyridin-4-yl)-ethyl]-5-trifluoromethyl-benzamide B20N-(4-tert-Butyl-benzyl)-3-chloro-N-[2-(2-chloro- 527.1 [ISP(M + H)⁺]pyridin-4-yl)-ethyl]-2-fluoro-5-trifluoromethyl- benzamide B21N-(4-tert-Butyl-benzyl)-3-chloro-N-[2-(4-chloro-3- 566.2 [ISP(M + H)⁺]trifluoromethyl-pyrazol-1-yl)-ethyl]-5- trifluoromethyl-benzamide B22N-(4-tert-Butyl-benzyl)-3-chloro-N-[2-(4-chloro-3- 584.1 [ISP(M + H)⁺]trifluoromethyl-pyrazol-1-yl)-ethyl]-2-fluoro-5-trifluoromethyl-benzamide B23N-(4-tert-Butyl-benzyl)-3-chloro-5-trifluoromethyl- 543.1 [ISP(M + H)⁺]N-[2-(6-trifluoromethyl-pyridin-2-yl)-ethyl]- benzamide B24N-(4-tert-Butyl-benzyl)-3-chloro-2-fluoro-5- 561 [ISP(M + H)⁺]trifluoromethyl-N-[2-(6-trifluoromethyl-pyridin-2- yl)-ethyl]-benzamideB25 N-(4-tert-Butyl-benzyl)-3-chloro-2-fluoro-N- 492 [ISP(M + H)⁺]phenethyl-5-trifluoromethyl-benzamide B26N-(4-tert-Butyl-benzyl)-3-chloro-N-[2-(3,4-dichloro- 559.8 [ISP(M + H)⁺]phenyl)-ethyl]-2-fluoro-5-trifluoromethyl-benzamide B27N-(4-tert-Butyl-benzyl)-3-chloro-2-fluoro-N-(2-p- 506 [ISP(M + H)⁺]tolyl-ethyl)-5-trifluoromethyl-benzamide B28N-(4-tert-Butyl-benzyl)-3-chloro-2-fluoro-N-[2-(4- 510.3 [ISP(M + H)⁺]fluoro-phenyl)-ethyl]-5-trifluoromethyl-benzamide B29N-(4-tert-Butyl-benzyl)-3-chloro-N-[2-(3-chloro- 526.1 [ISP(M + H)⁺]phenyl)-ethyl]-2-fluoro-5-trifluoromethyl-benzamide B30N-(4-tert-Butyl-benzyl)-3-chloro-2-fluoro-5- 560.3 [ISP(M + H)⁺]trifluoromethyl-N-[2-(3-trifluoromethyl-phenyl)- ethyl]-benzamide B31N-(4-tert-Butyl-benzyl)-3-chloro-N-[2-(3,4-dichloro- 492.2 [ISP(M + H)⁺]phenyl)-ethyl]-2-fluoro-benzamide B32N-(4-tert-Butyl-benzyl)-3-chloro-2-fluoro-N-[2-(3- 491.3 [ISP(M + H)⁺]trifluoromethyl-phenyl)-ethyl]-benzamide B33N-(4-tert-Butyl-benzyl)-3,5-bis-trifluoromethyl-N-[2- 576.1 [ISP(M +H)⁺] (3-trifluoromethyl-phenyl)-ethyl]-benzamide B34N-(4-tert-Butyl-benzyl)-2,6-difluoro-3- 544.3 [ISP(M + H)⁺]trifluoromethyl-N-[2-(3-trifluoromethyl-phenyl)- ethyl]-benzamide B35N-(4-tert-Butyl-benzyl)-2,4,6-trifluoro-N-[2-(3- 494.5 [ISP(M + H)⁺]trifluoromethyl-phenyl)-ethyl]-benzamide B36N-(4-tert-Butyl-benzyl)-2-fluoro-5-iodo-N-[2-(3- 584.2 [ISP(M + H)⁺]trifluoromethyl-phenyl)-ethyl]-benzamide B37N-(4-tert-Butyl-benzyl)-5-chloro-2,3,4-trifluoro-N- 528.3 [ISP(M + H)⁺][2-(3-trifluoromethyl-phenyl)-ethyl]-benzamide B38N-(4-tert-Butyl-benzyl)-3-chloro-2-fluoro-5-hydroxy- 508.5 [ISP(M + H)⁺]N-[2-(3-trifluoromethyl-phenyl)-ethyl]-benzamide B39N-(4-tert-Butyl-benzyl)-5-chloro-2-fluoro-N-[2-(3- 492.1 [ISP(M + H)⁺]trifluoromethyl-phenyl)-ethyl]-benzamide B40N-(4-tert-Butyl-benzyl)-3,5-dichloro-2-hydroxy-N-[2- 523.2 [ISP(M + H)⁺](3-trifluoromethyl-phenyl)-ethyl]-benzamide B41N-(4-tert-Butyl-benzyl)-3-chloro-2-fluoro-N-[2-(3- 576.1 [ISP(M + H)⁺]trifluoromethoxy-phenyl)-ethyl]-5-trifluoromethyl- benzamide B42N-(4-tert-Butyl-benzyl)-2,5-dichloro-N-[2-(3- 508.3 [ISP(M + H)⁺]trifluoromethyl-phenyl)-ethyl]-benzamide B43N-(4-tert-Butyl-benzyl)-5-chloro-2-trifluoromethyl- 542.2 [ISP(M + H)⁺]N-[2-(3-trifluoromethyl-phenyl)-ethyl]-benzamide B44N-(4-tert-Butyl-benzyl)-3-chloro-5-fluoro-N-[2-(3- 492.1 [ISP(M + H)⁺]trifluoromethyl-phenyl)-ethyl]-benzamide B45N-(4-tert-Butyl-benzyl)-3,5-dichloro-N-[2-(3- 508.3 [ISP(M + H)⁺]trifluoromethyl-phenyl)-ethyl]-benzamide B46N-(4-tert-Butyl-benzyl)-3-fluoro-5-trifluoromethyl- 526.3 [ISP(M + H)⁺]N-[2-(3-trifluoromethyl-phenyl)-ethyl]-benzamide B47N-(4-tert-Butyl-benzyl)-2,3-dichloro-N-[2-(3- 508.3 [ISP(M + H)⁺]trifluoromethyl-phenyl)-ethyl]-benzamide B48N-(4-tert-Butyl-benzyl)-3-chloro-5-trifluoromethyl- 542.2 [ISP(M + H)⁺]N-[2-(3-trifluoromethyl-phenyl)-ethyl]-benzamide B49N-(4-tert-Butyl-benzyl)-3,5-dichloro-N-[2-(3- 524.1 [ISP(M + H)⁺]trifluoromethoxy-phenyl)-ethyl]-benzamide B50N-(4-tert-Butyl-benzyl)-3,5-dichloro-N-[2-(4-fluoro- 458.2 [ISP(M + H)⁺]phenyl)-ethyl]-benzamide B51 N-(4-tert-Butyl-benzyl)-3-chloro-N-[2-(3-558.2 [ISP(M + H)⁺] trifluoromethoxy-phenyl)-ethyl]-5-trifluoromethyl-benzamide B52 N-(4-tert-Butyl-benzyl)-3-chloro-N-[2-(4-fluoro- 492.1[ISP(M + H)⁺] phenyl)-ethyl]-5-trifluoromethyl-benzamide B53N-(4-tert-Butyl-benzyl)-3-chloro-N-[2-(4-chloro- 508.3 [ISP(M + H)⁺]phenyl)-ethyl]-5-trifluoromethyl-benzamide B54N-(4-tert-Butyl-benzyl)-3-fluoro-N-[2-(3- 542.2 [ISP(M + H)⁺]trifluoromethoxy-phenyl)-ethyl]-5-trifluoromethyl- benzamide B55N-(4-tert-Butyl-benzyl)-N-[2-(4-chloro-phenyl)- 492.1 [ISP(M + H)⁺]ethyl]-3-fluoro-5-trifluoromethyl-benzamide B56N-(4-tert-Butyl-benzyl)-3,5-dimethyl-N-[2-(3- 468.5 [ISP(M + H)⁺]trifluoromethyl-phenyl)-ethyl]-benzamide B57N-(4-tert-Butyl-benzyl)-2-fluoro-5-trifluoromethyl- 526.3 [ISP(M + H)⁺]N-[2-(3-trifluoromethyl-phenyl)-ethyl]-benzamide B58N-(4-tert-Butyl-benzyl)-3-chloro-4-fluoro-5- 560.3 [ISP(M + H)⁺]trifluoromethyl-N-[2-(3-trifluoromethyl-phenyl)- ethyl]-benzamide B59N-(4-tert-Butyl-benzyl)-3-chloro-N-[2-(3-fluoro-5- 560.3 [ISP(M + H)⁺]trifluoromethyl-phenyl)-ethyl]-5-trifluoromethyl- benzamide B60N-(4-tert-Butyl-benzyl)-3-chloro-N-[2-(4-fluoro-3- 560.3 [ISP(M + H)⁺]trifluoromethyl-phenyl)-ethyl]-5-trifluoromethyl- benzamide B61N-(4-tert-Butyl-benzyl)-4-chloro-3-trifluoromethyl- 542.1 [ISP(M + H)⁺]N-[2-(3-trifluoromethyl-phenyl)-ethyl]-benzamide B62N-(4-tert-Butyl-benzyl)-3-chloro-N-[2-(3,4-dichloro- 542.2 [ISP(M + H)⁺]phenyl)-ethyl]-5-trifluoromethyl-benzamide B63N-(4-tert-Butyl-benzyl)-3-chloro-2-fluoro-N-[2-(3- 578.3 [ISP(M + H)⁺]fluoro-5-trifluoromethyl-phenyl)-ethyl]-5- trifluoromethyl-benzamide B64N-(4-tert-Butyl-benzyl)-3-fluoro-N-[2-(3-fluoro-5- 544.3 [ISP(M + H)⁺]trifluoromethyl-phenyl)-ethyl]-5-trifluoromethyl- benzamide B65N-(4-tert-Butyl-benzyl)-3-chloro-2-fluoro-N-[2-(4- 578.2 [ISP(M + H)⁺]fluoro-3-trifluoromethyl-phenyl)-ethyl]-5- trifluoromethyl-benzamide B66N-(4-tert-Butyl-benzyl)-3-chloro-N-(3-phenyl- 488.1 [ISP(M + H)⁺]propyl)-5-trifluoromethyl-benzamide B67N-(4-tert-Butyl-benzyl)-3,5-dichloro-4-fluoro-N-[2- 526.2 [ISP(M + H)⁺](3-trifluoromethyl-phenyl)-ethyl]-benzamide B68N-(4-tert-Butyl-benzyl)-3,5-dichloro-N-[2-(3-fluoro- 526 [ISP(M + H)⁺]5-trifluoromethyl-phenyl)-ethyl]-benzamide B69N-(4-tert-Butyl-benzyl)-3,5-dichloro-N-[2-(4-fluoro- 526 [ISP(M + H)⁺]3-trifluoromethyl-phenyl)-ethyl]-benzamide B70N-(4-tert-Butyl-benzyl)-3,5-dichloro-4-fluoro-N-[2- 544.1 [ISP(M + H)⁺](3-fluoro-5-trifluoromethyl-phenyl)-ethyl]-benzamide B71N-(4-tert-Butyl-benzyl)-3,5-dichloro-N-[2-(3,4- 508.2 [ISP(M + H)⁺]dichloro-phenyl)-ethyl]-benzamide B72N-(4-tert-Butyl-benzyl)-3-chloro-N-[2-(3- 514.2 [ISP(M + H)⁺]cyclopropyl-phenyl)-ethyl]-5-trifluoromethyl- benzamide B73N-(4-tert-Butyl-benzyl)-3-chloro-N-[2-(3-chloro-5- 548.1 [ISP(M + H)⁺]cyclopropyl-phenyl)-ethyl]-5-trifluoromethyl- benzamide B74N-(4-tert-Butyl-benzyl)-3-chloro-N-[2-(3-chloro-5- 566.2 [ISP(M + H)⁺]cyclopropyl-phenyl)-ethyl]-2-fluoro-5- trifluoromethyl-benzamide B75N-(4-tert-Butyl-benzyl)-3-chloro-N-[2-(3- 550.2 [ISP(M + H)⁺]cyclopropyl-5-fluoro-phenyl)-ethyl]-2-fluoro-5-trifluoromethyl-benzamide B76N-(4-tert-Butyl-benzyl)-3-chloro-5-cyclopropyl-N-[2- 532.1 [ISP(M + H)⁺](3-fluoro-5-trifluoromethyl-phenyl)-ethyl]-benzamide B77N-(4-tert-Butyl-benzyl)-3-chloro-5-cyclopropyl-N-[2- 514.2 [ISP(M + H)⁺](3-trifluoromethyl-phenyl)-ethyl]-benzamide B78N-(4-tert-Butyl-benzyl)-3-chloro-N-[2-(3-chloro-5- 594.2 [ISP(M + H)⁺]trifluoromethyl-phenyl)-ethyl]-2-fluoro-5- trifluoromethyl-benzamide B79N-(4-tert-Butyl-benzyl)-3-chloro-N-[2-(3-chloro-5- 576.3 [ISP(M + H)⁺]trifluoromethyl-phenyl)-ethyl]-5-trifluoromethyl- benzamide B80N-(4-tert-Butyl-benzyl)-3-chloro-N-[2-(4-chloro-3- 526 [ISP(M + H)⁺]fluoro-phenyl)-ethyl]-5-trifluoromethyl-benzamide B813-Chloro-N-[2-(4-chloro-phenyl)-ethyl]-2-fluoro-N- 638.1 [ISP(M + H)⁺][4-(1,2,2,2-tetrafluoro-1-trifluoromethyl-ethyl)-benzyl]-5-trifluoromethyl-benzamide B823-Chloro-2-fluoro-N-[2-(4-fluoro-phenyl)-ethyl]-N- 572.1 [ISP(M + H)⁺](4-pentafluoroethyl-benzyl)-5-trifluoromethyl- benzamide B83N-(4-tert-Butyl-benzyl)-2-chloro-5-trifluoromethyl- 542.3 [ISP(M + H)⁺]N-[2-(3-trifluoromethyl-phenyl)-ethyl]-benzamide B84N-(4-tert-Butyl-benzyl)-3,5-difluoro-N-[2-(3- 476 [ISP(M + H)⁺]trifluoromethyl-phenyl)-ethyl]-benzamide B85N-(4-tert-Butyl-benzyl)-3,5-dichloro-N-[2-(4-chloro- 474 [ISP(M + H)⁺]phenyl)-ethyl]-benzamide B86N-(4-tert-Butyl-benzyl)-3-chloro-2-fluoro-5- 560.3 [ISP(M + H)⁺]trifluoromethyl-N-[2-(4-trifluoromethyl-phenyl)- ethyl]-benzamide B87N-(4-tert-Butyl-benzyl)-3-fluoro-N-[2-(4-fluoro- 476 [ISP(M + H)⁺]phenyl)-ethyl]-5-trifluoromethyl-benzamide B883-Chloro-N-(4-cyclobutyl-benzyl)-2-fluoro-N-[2-(3- 574.3 [ISP(M + H)⁺]trifluoromethoxy-phenyl)-ethyl]-5-trifluoromethyl- benzamide B893-Chloro-N-(4-cyclobutyl-benzyl)-N-[2-(3- 556.2 [ISP(M + H)⁺]trifluoromethoxy-phenyl)-ethyl]-5-trifluoromethyl- benzamide B90N-(4-Cyclobutyl-benzyl)-3-fluoro-N-[2-(3- 540.3 [ISP(M + H)⁺]trifluoromethoxy-phenyl)-ethyl]-5-trifluoromethyl- benzamide B913,5-Dichloro-N-(4-cyclobutyl-benzyl)-N-[2-(3- 552.3 [ISP(M + H)⁺]trifluoromethoxy-phenyl)-ethyl]-benzamide B923-Chloro-N-(4-cyclobutyl-benzyl)-2-fluoro-5- 558 [ISP(M + H)⁺]trifluoromethyl-N-[2-(3-trifluoromethyl-phenyl)- ethyl]-benzamide B933-Chloro-N-(4-cyclobutyl-benzyl)-5-trifluoromethyl- 540.2 [ISP(M + H)⁺]N-[2-(3-trifluoromethyl-phenyl)-ethyl]-benzamide B94N-(4-Cyclobutyl-benzyl)-3-fluoro-5-trifluoromethyl- 524.2 [ISP(M + H)⁺]N-[2-(3-trifluoromethyl-phenyl)-ethyl]-benzamide B953,5-Dichloro-N-(4-cyclobutyl-benzyl)-N-[2-(3- 506.1 [ISP(M + H)⁺]trifluoromethyl-phenyl)-ethyl]-benzamide B963-Chloro-N-[2-(4-chloro-phenyl)-ethyl]-N-(4- 524.2 [ISP(M + H)⁺]cyclobutyl-benzyl)-2-fluoro-5-trifluoromethyl- benzamide B973-Chloro-N-[2-(4-chloro-phenyl)-ethyl]-N-(4- 506.2 [ISP(M + H)⁺]cyclobutyl-benzyl)-5-trifluoromethyl-benzamide B98N-[2-(4-Chloro-phenyl)-ethyl]-N-(4-cyclobutyl- 490.3 [ISP(M + H)⁺]benzyl)-3-fluoro-5-trifluoromethyl-benzamide B993,5-Dichloro-N-[2-(4-chloro-phenyl)-ethyl]-N-(4- 472 [ISP(M + H)⁺]cyclobutyl-benzyl)-benzamide B1003-Chloro-N-(4-cyclobutyl-benzyl)-2-fluoro-N-[2-(4- 508.4 [ISP(M + H)⁺]fluoro-phenyl)-ethyl]-5-trifluoromethyl-benzamide B1013-Chloro-N-(4-cyclobutyl-benzyl)-N-[2-(4-fluoro- 490.3 [ISP(M + H)⁺]phenyl)-ethyl]-5-trifluoromethyl-benzamide B102N-(4-Cyclobutyl-benzyl)-3-fluoro-N-[2-(4-fluoro- 474.1 [ISP(M + H)⁺]phenyl)-ethyl]-5-trifluoromethyl-benzamide B1033,5-Dichloro-N-(4-cyclobutyl-benzyl)-N-[2-(4-fluoro- 456.2 [ISP(M + H)⁺]phenyl)-ethyl]-benzamide B1043,5-Dichloro-N-[2-(4-chloro-phenyl)-ethyl]-N-[4- 586.1 [ISP(M + H)⁺](1,2,2,2-tetrafluoro-1-trifluoromethyl-ethyl)-benzyl]- benzamide B1053-Chloro-N-[2-(4-chloro-phenyl)-ethyl]-N-[4- 620.2 [ISP(M + H)⁺](1,2,2,2-tetrafluoro-1-trifluoromethyl-ethyl)-benzyl]-5-trifluoromethyl-benzamide B1063-Chloro-N-[2-(4-chloro-phenyl)-ethyl]-N-[4-(1,1- 540.3 [ISP(M + H)⁺]dimethyl-propyl)-benzyl]-2-fluoro-5-trifluoromethyl- benzamide B1073-Chloro-N-[2-(4-chloro-phenyl)-ethyl]-N-[4-(1,1- 522.2 [ISP(M + H)⁺]dimethyl-propyl)-benzyl]-5-trifluoromethyl- benzamide B1083,5-Dichloro-N-[2-(4-chloro-phenyl)-ethyl]-N-[4- 488.1 [ISP(M + H)⁺](1,1-dimethyl-propyl)-benzyl]-benzamide B1093-Chloro-2-fluoro-5-trifluoromethyl-N-[2-(3- 576.4 [ISP(M + H)⁺]trifluoromethyl-phenyl)-ethyl]-N-(4-trimethylsilanyl- benzyl)-benzamideB110 3-Chloro-N-[2-(4-chloro-phenyl)-ethyl]-2-fluoro-5- 542.2 [ISP(M +H)⁺] trifluoromethyl-N-(4-trimethylsilanyl-benzyl)- benzamide B1113-Chloro-2-fluoro-N-[2-(4-fluoro-phenyl)-ethyl]-5- 526.2 [ISP(M + H)⁺]trifluoromethyl-N-(4-trimethylsilanyl-benzyl)- benzamide B1123-Chloro-N-[2-(3,4-dichloro-phenyl)-ethyl]-2-fluoro- 576.3 [ISP(M + H)⁺]5-trifluoromethyl-N-(4-trimethylsilanyl-benzyl)- benzamide B1133-Chloro-2-fluoro-N-[2-(3-trifluoromethoxy-phenyl)- 592.3 [ISP(M + H)⁺]ethyl]-5-trifluoromethyl-N-(4-trimethylsilanyl- benzyl)-benzamide B1143-Chloro-2-fluoro-N-[2-(3-trifluoromethyl-phenyl)- 508.4 [ISP(M + H)⁺]ethyl]-N-(4-trimethylsilanyl-benzyl)-benzamide B1153-Chloro-N-[2-(4-chloro-phenyl)-ethyl]-2-fluoro-N- 474.2 [ISP(M + H)⁺](4-trimethylsilanyl-benzyl)-benzamide B1163-Chloro-2-fluoro-N-[2-(4-fluoro-phenyl)-ethyl]-N- 458.4 [ISP(M + H)⁺](4-trimethylsilanyl-benzyl)-benzamide B1173-Chloro-N-[2-(3,4-dichloro-phenyl)-ethyl]-2-fluoro- 508.3 [ISP(M + H)⁺]N-(4-trimethylsilanyl-benzyl)-benzamide B1185-Chloro-N-[2-(4-chloro-phenyl)-ethyl]-2-fluoro-N- 474.2 [ISP(M + H)⁺](4-trimethylsilanyl-benzyl)-benzamide B1193,5-Dichloro-N-[2-(3-trifluoromethyl-phenyl)-ethyl]- 524.4 [ISP(M + H)⁺]N-(4-trimethylsilanyl-benzyl)-benzamide B1203,5-Dichloro-N-[2-(4-chloro-phenyl)-ethyl]-N-(4- 490.2 [ISP(M + H)⁺]trimethylsilanyl-benzyl)-benzamide B1213,5-Dichloro-N-[2-(4-fluoro-phenyl)-ethyl]-N-(4- 474.2 [ISP(M + H)⁺]trimethylsilanyl-benzyl)-benzamide B1223,5-Dichloro-N-[2-(3,4-dichloro-phenyl)-ethyl]-N-(4- 526.2 [ISP(M + H)⁺]trimethylsilanyl-benzyl)-benzamide B1233-Chloro-N-[2-(4-chloro-phenyl)-ethyl]-5- 524.4 [ISP(M + H)⁺]trifluoromethyl-N-(4-trimethylsilanyl-benzyl)- benzamide B1243-Chloro-N-[2-(4-fluoro-phenyl)-ethyl]-5- 508.4 [ISP(M + H)⁺]trifluoromethyl-N-(4-trimethylsilanyl-benzyl)- benzamide B1253-Chloro-N-[2-(3,4-dichloro-phenyl)-ethyl]-5- 558.1 [ISP(M + H)⁺]trifluoromethyl-N-(4-trimethylsilanyl-benzyl)- benzamide B1263-Chloro-N-[4-(1,1-dimethyl-propyl)-benzyl]-5- 556.2 [ISP(M + H)⁺]trifluoromethyl-N-[2-(3-trifluoromethyl-phenyl)- ethyl]-benzamide B1273-Chloro-5-trifluoromethyl-N-[2-(3-trifluoromethyl- 558 [ISP(M + H)⁺]phenyl)-ethyl]-N-(4-trimethylsilanyl-benzyl)- benzamide B1283-Chloro-N-(4-cyclopropyl-benzyl)-N-[2-(3,4- 526.1 [ISP(M + H)⁺]dichloro-phenyl)-ethyl]-5-trifluoromethyl-benzamide B1293-Chloro-N-[2-(4-chloro-phenyl)-ethyl]-5- 520 [ISP(M + H)⁺]trifluoromethyl-N-(4-trifluoromethyl-benzyl)- benzamide B1303-Chloro-N-[2-(4-chloro-phenyl)-ethyl]-N-(4- 536 [ISP(M + H)⁺]trifluoromethoxy-benzyl)-5-trifluoromethyl- benzamide B1313-Chloro-N-[2-(4-chloro-phenyl)-ethyl]-N-[4-(1- 524.1 [ISP(M + H)⁺]fluoro-cyclobutyl)-benzyl]-5-trifluoromethyl- benzamide B1323-Chloro-N-[4-(1-fluoro-cyclobutyl)-benzyl]-N-[2- 508.1 [ISP(M + H)⁺](4-fluoro-phenyl)-ethyl]-5-trifluoromethyl-benzamide B1333-Chloro-N-[2-(3-chloro-phenyl)-ethyl]-N-[4-(1- 524.1 [ISP(M + H)⁺]fluoro-cyclobutyl)-benzyl]-5-trifluoromethyl- benzamide B1343-Chloro-N-[4-(1-fluoro-cyclobutyl)-benzyl]-5- 558 [ISP(M + H)⁺]trifluoromethyl-N-[2-(3-trifluoromethyl-phenyl)- ethyl]-benzamide B1353-Chloro-N-[2-(4-chloro-phenyl)-ethyl]-2-fluoro-N- 542.2 [ISP(M + H)⁺][4-(1-fluoro-cyclobutyl)-benzyl]-5-trifluoromethyl- benzamide B1363-Chloro-2-fluoro-N-[4-(1-fluoro-cyclobutyl)- 526.2 [ISP(M + H)⁺]benzyl]-N-[2-(4-fluoro-phenyl)-ethyl]-5- trifluoromethyl-benzamide B1373-Chloro-N-[2-(3-chloro-phenyl)-ethyl]-2-fluoro-N- 542.2 [ISP(M + H)⁺][4-(1-fluoro-cyclobutyl)-benzyl]-5-trifluoromethyl- benzamide B1383-Chloro-2-fluoro-N-[4-(1-fluoro-cyclobutyl)- 576.3 [ISP(M + H)⁺]benzyl]-5-trifluoromethyl-N-[2-(3-trifluoromethyl-phenyl)-ethyl]-benzamide B139N-(4-tert-Butyl-benzyl)-2-chloro-N-[2-(3,5-dichloro- 542 [EI(M)⁺]phenyl)-ethyl]-6-trifluoromethyl-isonicotinamide B140N-(4-tert-Butyl-benzyl)-3-chloro-N-[2-(3,5-dichloro- 541 [EI(M)⁺]phenyl)-ethyl]-5-trifluoromethyl-benzamide B141N-(4-tert-Butyl-benzyl)-3-chloro-N-[2-(3,5-dichloro- 560.2 [ISP(M + H)⁺]phenyl)-ethyl]-2-fluoro-5-trifluoromethyl-benzamide B142N-(4-tert-Butyl-benzyl)-3-chloro-N-[2-(4-chloro-3- 593.1 [EI(M)⁺]trifluoromethyl-phenyl)-ethyl]-2-fluoro-5- trifluoromethyl-benzamideB143 N-(4-tert-Butyl-benzyl)-3-chloro-N-[2-(4-chloro-3- 575.1 [EI(M)⁺]trifluoromethyl-phenyl)-ethyl]-5-trifluoromethyl- benzamide B144N-(4-tert-Butyl-benzyl)-3-chloro-N-[2-(3-chloro-5- 544.1 [ISP(M + H)⁺]fluoro-phenyl)-ethyl]-2-fluoro-5-trifluoromethyl- benzamide B145N-(4-tert-Butyl-benzyl)-3-chloro-N-[2-(3-chloro-5- 526.2 [ISP(M + H)⁺]fluoro-phenyl)-ethyl]-5-trifluoromethyl-benzamide B146N-(4-tert-Butyl-benzyl)-2-chloro-N-[2-(3-chloro-4- 527.0 [ISP(M + H)⁺]fluoro-phenyl)-ethyl]-6-trifluoromethyl- isonicotinamide B147N-(4-tert-Butyl-benzyl)-2-chloro-N-[2-(4-chloro-3- 576.2 [EI(M)⁺]trifluoromethyl-phenyl)-ethyl]-6-trifluoromethyl- isonicotinamide B148N-[2-(3,5-Bis-trifluoromethyl-phenyl)-ethyl]-N-(4- 627.2 [EI(M)⁺]tert-butyl-benzyl)-3-chloro-2-fluoro-5- trifluoromethyl-benzamide B1496-Chloro-4-trifluoromethyl-pyridine-2-carboxylic acid 543 [ISP(M + H)⁺](4-tert-butyl-benzyl)-[2-(3-trifluoromethyl-phenyl)- ethyl]-amide B1506-Chloro-4-trifluoromethyl-pyridine-2-carboxylic acid 561.2 [ISP(M +H)⁺] (4-tert-butyl-benzyl)-[2-(3-fluoro-5-trifluoromethyl-phenyl)-ethyl]-amide B1516-Chloro-4-trifluoromethyl-pyridine-2-carboxylic acid 543.1 [ISP(M +H)⁺] (4-tert-butyl-benzyl)-[2-(3,4-dichloro-phenyl)-ethyl]- amide B1526-Chloro-4-trifluoromethyl-pyridine-2-carboxylic acid 561.2 [ISP(M +H)⁺] (4-tert-butyl-benzyl)-[2-(3-fluoro-4-trifluoromethyl-phenyl)-ethyl]-amide B153 N-(4-tert-Butyl-benzyl)-3-chloro-N-[2-(3-550.3 [ISP(M + H)⁺] cyclopropyl-4-fluoro-phenyl)-ethyl]-2-fluoro-5-trifluoromethyl-benzamide B1546-Methyl-2-trifluoromethyl-pyrimidine-4-carboxylic 524.4 [ISP(M + H)⁺]acid (4-tert-butyl-benzyl)-[2-(3-trifluoromethyl- phenyl)-ethyl]-amideB155 N-Butyl-N-(4-tert-butyl-benzyl)-3-chloro-2-fluoro-5- 444.4 [ISP(M +H)⁺] trifluoromethyl-benzamide B156N-Butyl-N-(4-tert-butyl-benzyl)-3-fluoro-5- 409.2 [EI(M)⁺]trifluoromethyl-benzamide B157N-Butyl-N-(4-tert-butyl-benzyl)-2-fluoro-5- 410.5 [ISP(M + H)⁺]trifluoromethyl-benzamide B158N-(4-tert-Butyl-benzyl)-2,3,5-trichloro-N-[2-(3-tri- 542.0 [ISP(M + H)⁺]fluoromethyl-phenyl)-ethyl]-benzamide B159N-(4-tert-Butyl-benzyl)-2,3,5-trichloro-N-[2-(3- 561.9 [ISP(M + H)⁺]fluoro-5-trifluoromethyl-phenyl)-ethyl]-benzamide B160N-(4-tert-Butyl-benzyl)-3-chloro-N-[2-(3-chloro-4- 526.1 [ISP(M + H)⁺]fluoro-phenyl)-ethyl]-5-trifluoromethyl-benzamide B161N-(4-tert-Butyl-benzyl)-3-chloro-N-[2-(3-chloro-4- 544.2 [ISP(M + H)⁺]fluoro-phenyl)-ethyl]-2-fluoro-5-trifluoromethyl- benzamide B162N-(4-tert-Butyl-benzyl)-3-chloro-N-[2-(4-chloro-3- 544.3 [ISP(M + H)⁺]fluoro-phenyl)-ethyl]-2-fluoro-5-trifluoromethyl- benzamide B163N-[2-(3-Bromo-phenyl)-ethyl]-N-(4-tert-butyl- 554.1 [ISP(M + H)⁺]benzyl)-3-chloro-5-trifluoromethyl-benzamide B164N-(4-tert-Butyl-benzyl)-3-chloro-N-[2-(3-ethyl- 520.4 [ISP(M + H)⁺]phenyl)-ethyl]-2-fluoro-5-trifluoromethyl-benzamide B165N-(4-tert-Butylbenzyl)-3-chloro-N-[2-(3-cyclopropyl- 532.3 [ISP(M + H)⁺]4-fluorophenyl)-ethyl]-5-trifluoromethyl-benzamide B166N-(4-tert-Butylbenzyl)-3-chloro-N-[2-(3,4- 572.3 [ISP(M + H)⁺]dicyclopropylphenyl)-ethyl]-2-fluoro-5- trifluoromethyl-benzamide B167N-(4-tert-Butylbenzyl)-3-chloro-N-[2-(4-chloro-3- 566.2 [ISP(M + H)⁺]cyclopropylphenyl)-ethyl]-2-fluoro-5-trifluoromethyl- benzamide B168N-(4-tert-Butylbenzyl)-3-chloro-N-[2-(4-chloro-3- 550.4 [ISP(M + H)⁺]isopropylphenyl)-ethyl]-5-trifluoromethyl-benzamide B169N-(4-tert-Butylbenzyl)-3-chloro-N-[2-(4-chloro-3- 568.2 [ISP(M + H)⁺]isopropylphenyl)-ethyl]-2-fluoro-5-trifluoromethyl- benzamide B170N-(4-tert-Butyl-benzyl)-3-chloro-2-fluoro-5- 574.4 [ISP(M + H)⁺]trifluoromethyl-N-[3-(3-trifluoromethyl-phenyl)- propyl]-benzamide B171N-(4-tert-Butyl-benzyl)-3-chloro-N-[2-(4-chloro-3- 554.3 [ISP(M + H)⁺]ethyl-phenyl)-ethyl]-2-fluoro-5-trifluoromethyl- benzamide B172N-(4-tert-Butyl-benzyl)-3-chloro-N-[3-(3-chloro- 540.3 [ISP(M + H)⁺]phenyl)-propyl]-2-fluoro-5-trifluoromethyl- benzamide B173N-(4-tert-Butyl-benzyl)-3-chloro-N-[3-(3-chloro- 522.2 [ISP(M + H)⁺]phenyl)-propyl]-5-trifluoromethyl-benzamide B174N-(4-tert-Butyl-benzyl)-3-chloro-N-[3-(4-chloro- 540.3 [ISP(M + H)⁺]phenyl)-propyl]-2-fluoro-5-trifluoromethyl- benzamide B175N-(4-tert-Butyl-benzyl)-3-chloro-N-[3-(4-chloro- 522.2 [ISP(M + H)⁺]phenyl)-propyl]-5-trifluoromethyl-benzamide B1763-Bromo-N-(4-tert-butyl-benzyl)-5-chloro-N-[2-(3- 552 [ISP(M + H)⁺]trifluoromethyl-phenyl)-ethyl]-benzamide B1773-Bromo-N-(4-tert-butyl-benzyl)-5-chloro-N-[2-(3- 570.3 [ISP(M + H)⁺]fluoro-5-trifluoromethyl-phenyl)-ethyl]-benzamide B178N-[2-(3-Bromo-4-fluoro-phenyl)-ethyl]-N-(4-tert- 590.3 [ISP(M + H)⁺]butyl-benzyl)-3-chloro-2-fluoro-5-trifluoromethyl- benzamide

EXAMPLE 2N-(4-tert-butyl-benzyl)-3-chloro-2-fluoro-N-[2-(3-hydroxy-phenyl)-ethyl]-5-trifluoromethyl-benzamidea) Preparation ofN-[2-(3-benzyloxy-phenyl)-ethyl]-N-(4-tert-butyl-benzyl)-3-chloro-2-fluoro-5-trifluoromethyl-benzamide

The title compound was prepared in analogy to Example 1, using[2-(3-benzyloxy-phenyl)-ethyl]-(4-tert-butyl-benzyl)-amine (S9-C43) and3-chloro-2-fluoro-5-(trifluoromethyl)benzoic acid. MS: 597.3 [ISP(M+H)⁺].

b) Preparation ofN-(4-tert-butyl-benzyl)-3-chloro-2-fluoro-N-[2-(3-hydroxy-phenyl)-ethyl]-5-trifluoromethyl-benzamide

A solution of 1.1 g ofN-[2-(3-benzyloxy-phenyl)-ethyl]-N-(4-tert-butyl-benzyl)-3-chloro-2-fluoro-5-trifluoromethyl-benzamide(1.84 mmol) in 50 ml ethyl acetate was hydrogenated over 0.33 g Pd/C-5%.After completion of the reaction the suspension was filtered off andconcentrated in vacuo to give 0.75 g of a colorless amorphous material.MS: 508.4 [ISP (M+H)⁺].

EXAMPLE 3N-(4-tert-butyl-benzyl)-3-chloro-5-ethyl-N-[2-(3-fluoro-5-trifluoromethyl-phenyl)-ethyl]-benzamide

285 mg of3-bromo-N-(4-tert-butyl-benzyl)-5-chloro-N-[2-(3-fluoro-5-trifluoromethyl-phenyl)-ethyl]-benzamide(0.6 mmol, Example B177), 44 mg of ethylboronic acid (1.75 mmol), 371 mgof tri-potassium phosphate (0.05 mmol), 14 mg of tricyclohexylphosphineand 6 mg of palladium acetate were suspended in 2.3 ml toluene and 0.1ml water and stirred at 100° C. for 3.5 h under nitrogen. The reactionmixture was then cooled down to RT, diluted with 4 ml water andextracted twice with ethylacetate. The combined organic layers werewashed with brine, dried over magnesium sulfate, filtered off andconcentrated under vacuo. The resulting residue was purified by flashcolumn chromatography (Heptane/AcOEt:95/5) to yield 192 mg of a yellowsolid. MS (ISP) 520.3 (M+H)⁺.

EXAMPLE 3-bN-(4-tert-butyl-benzyl)-3-chloro-5-ethyl-N-[2-(3-trifluoromethyl-phenyl)-ethyl]-benzamide

The title compound was prepared in analogy to Example 3, using3-bromo-N-(4-tert-butyl-benzyl)-5-chloro-N-[2-(3-trifluoromethyl-phenyl)-ethyl]-benzamide(Example B176). MS (ISP) 502.3 (M+H)⁺.

EXAMPLE 3-cN-(4-tert-butyl-benzyl)-3-ethyl-2-fluoro-N-[2-(3-fluoro-5-trifluoromethyl-phenyl)-ethyl]-5-trifluoromethyl-benzamide

The title compound was prepared in analogy to example 3, usingN-(4-tert-butyl-benzyl)-3-chloro-2-fluoro-N-[2-(3-fluoro-5-trifluoromethyl-phenyl)-ethyl]-5-trifluoromethyl-benzamide(Example B63). MS (ISP) 572.3 (M+H)⁺.

EXAMPLE 3-dN-(4-tert-butyl-benzyl)-2-fluoro-N-[2-(3-fluoro-5-trifluoromethyl-phenyl)-ethyl]-5-trifluoromethyl-benzamide

The title compound was prepared in analogy to example 3, usingN-(4-tert-butyl-benzyl)-3-chloro-2-fluoro-N-[2-(3-fluoro-5-trifluoromethyl-phenyl)-ethyl]-5-trifluoromethyl-benzamide(Example B63). 544.2 [ISP (M+H)⁺]

EXAMPLE 3-eN-(4-tert-butyl-benzyl)-3-chloro-5-propyl-N-[2-(3-trifluoromethyl-phenyl)-ethyl]-benzamide

The title compound was prepared in analogy to example 3, using3-bromo-N-(4-tert-butyl-benzyl)-5-chloro-N-[2-(3-trifluoromethyl-phenyl)-ethyl]-benzamide(Example B176) and n-propylboronic acid. 516.2 [ISP (M+H)⁺]

EXAMPLE 3-fN-(4-tert-butyl-benzyl)-3-chloro-N-[2-(3-fluoro-5-trifluoromethyl-phenyl)-ethyl]-5-propyl-benzamide

The title compound was prepared in analogy to example 3, using3-bromo-N-(4-tert-butyl-benzyl)-5-chloro-N-[2-(3-fluoro-5-trifluoromethyl-phenyl)-ethyl]-benzamide(Example B177) and n-propylboronic acid. 534.3 [ISP (M+H)⁺]

EXAMPLE 3-gN-(4-tert-butyl-benzyl)-3-chloro-N-[2-(3-ethyl-4-fluoro-phenyl)-ethyl]-2-fluoro-5-trifluoromethyl-benzamide

The title compound was prepared in analogy to example 3, usingN-[2-(3-bromo-4-fluoro-phenyl)-ethyl]-N-(4-tert-butyl-benzyl)-3-chloro-2-fluoro-5-trifluoromethyl-benzamide(Example B178) and ethylboronic acid. 538.3 [ISP (M+H)⁺]

EXAMPLE 3-hN-(4-tert-butyl-benzyl)-3-chloro-2-fluoro-N-[2-(4-fluoro-3-propyl-phenyl)-ethyl]-5-trifluoromethyl-benzamide

The title compound was prepared in analogy to example 3, usingN-[2-(3-bromo-4-fluoro-phenyl)-ethyl]-N-(4-tert-butyl-benzyl)-3-chloro-2-fluoro-5-trifluoromethyl-benzamide(Example B178) and n-propylboronic acid. 552.2 [ISP (M+H)⁺]

EXAMPLE 4N-(4-tert-butyl-benzyl)-N-[2-(3-tert-butyl-4-hydroxy-phenyl)-ethyl]-3-chloro-2-fluoro-5-trifluoromethyl-benzamidea) Preparation ofN-[2-(4-benzyloxy-3-tert-butyl-phenyl)-ethyl]-N-(4-tert-butyl-benzyl)-3-chloro-2-fluoro-5-trifluoromethyl-benzamide

The title compound was prepared in analogy to Example 1, using[2-(4-benzyloxy-3-tert-butyl-phenyl)-ethyl]-(4-tert-butyl-benzyl)-amine(S9-C48) and 3-chloro-2-fluoro-5-(trifluoromethyl)benzoic acid. MS:654.4 [ISP (M+H)⁺].

b) Preparation ofN-(4-tert-butyl-benzyl)-N-[2-(3-tert-butyl-4-hydroxy-phenyl)-ethyl]-3-chloro-2-fluoro-5-trifluoromethyl-benzamide

A solution of 182 mg ofN-[2-(4-benzyloxy-3-tert-butyl-phenyl)-ethyl]-N-(4-tert-butyl-benzyl)-3-chloro-2-fluoro-5-trifluoromethyl-benzamide(0.278 mmol) in 15 ml ethyl acetate were hydrogenated over 100 mgPd/C-5%. After completion of the reaction the suspension was filteredoff and concentrated in vacuo. The resulting residue was purified byflash column chromatography (Heptane/AcOEt:90/10) to yield 130 mg of acolorless viscous oil. MS (ISP) 564 (M+H)⁺.

The compounds of formula I are cholesteryl ester transfer protein (CETP)inhibitors.

Atherosclerosis and its associated coronary heart disease is the leadingcause of death in the industrialized world. Risk for development ofcoronary heart disease has been shown to be strongly correlated withcertain plasma lipid levels. Lipids are transported in the blood bylipoproteins. The general structure of lipoproteins is a core of neutrallipids (triglyceride and cholesterol ester) and an envelope of polarlipids (phospholipids and non esterified cholesterol). There are threedifferent classes of plasma lipoproteins with different core lipidcontent: the low density lipoprotein (LDL) which is cholesteryl ester(CE) rich; high density lipoprotein (HDL) which is also cholesterylester (CE) rich; and the very low density lipoprotein (VLDL) which istriglyceride (TG) rich. The different lipoproteins can be separatedbased on their different flotation density or size.

High LDL-cholesterol (LDL-C) and triglyceride levels are positivelycorrelated, while high levels of HDL-cholesterol (HDL-C) are negativelycorrelated with the risk for developing cardiovascular diseases.

Plasma lipoprotein metabolism can be described as a flux of cholesterolbetween liver and the other tissues. The LDL pathway corresponds to thesecretion of VLDL from the liver to deliver cholesterol by LDL totissues. Any alteration in LDL catabolism could lead to uptake of excesscholesterol in the vessel wall forming foam cells and atherosclerosis.The opposite pathway is the mobilization of free cholesterol fromperipheral tissues by HDL to deliver cholesterol to the liver to beeventually excreted with bile. In humans a significant part ofcholesteryl ester (CE) is transferred from HDL to the VLDL, LDL pathway.This transfer is mediated by a 70,000 dalton plasma glycoprotein, thecholesteryl ester transfer protein (CETP).

Mutations in the CETP gene associated with CETP deficiency arecharacterized by high HDL-cholesterol levels (>60 mg/dL) and reducedcardiovascular risk. Such findings are consistent with studies ofpharmacologically mediated inhibition of CETP in the rabbit, which arguestrongly in favor of CETP inhibition as a valid therapeutic approach [LeGoff et al., Pharmacology & Therapeutics 101:17-38 (2004); Okamoto etal., Nature 406:203-207 2000)].

No wholly satisfactory HDL-elevating therapies exist. Niacin cansignificantly increase HDL, but has serious toleration issues whichreduce compliance. Fibrates and the HMG CoA reductase inhibitors raiseHDL-cholesterol only modestly (−10-12%). As a result, there is asignificant unmet medical need for a well tolerated agent which cansignificantly elevate plasma HDL levels. The net result of CETP activityis a lowering of HDL-C and an increase in LDL-C. This effect onlipoprotein profile is believed to be pro-atherogenic, especially insubjects whose lipid profile constitutes an increased risk for coronaryheart disease. Therefore by inhibiting CETP activity there is thepotential to inverse this relationship towards a lower risk andultimately to protect against coronary heart diseases and associatedmortality.

Thus, CETP inhibitors are useful as medicaments for the treatment and/orprophylaxis of atherosclerosis, peripheral vascular disease,dyslipidemia, hyperbeta-lipoproteinemia, hypoalphalipoproteinemia,hypercholesterolemia, hypertriglyceridemia, familialhypercholesterolemia, cardiovascular disorders, angina, ischemia,cardiac ischemia, stroke, myocardial infarction, reperfusion injury,angioplastic restenosis, hypertension, and vascular complications ofdiabetes, obesity or endotoxemia.

In addition, CETP inhibitors may be used in combination with anothercompound, said compound being an HMG-CoA reductase inhibitor, amicrosomal triglyceride transfer protein (MTP)/ApoB secretion inhibitor,a PPAR activator, a bile acid reuptake inhibitor, a cholesterolabsorption inhibitor, a cholesterol synthesis inhibitor, a fibrate,niacin, an ion-exchange resin, an antioxidant, an ACAT inhibitor or abile acid sequestrant.

As described above, the compounds of formula I of the present inventioncan be used as medicaments for the treatment and/or prophylaxis ofdiseases which are mediated by CETP. Examples of such diseases areatherosclerosis, peripheral vascular disease, dyslipidemia,hyperbetalipoproteinemia, hypoalphalipoproteinemia,hypercholesterolemia, hypertriglyceridemia, familialhypercholesterolemia, cardiovascular disorders, angina, ischemia,cardiac ischemia, stroke, myocardial infarction, reperfusion injury,angioplastic restenosis, hypertension, and vascular complications ofdiabetes, obesity or endotoxemia. The use as medicament for thetreatment and/or prevention of dyslipidemia is preferred.

The invention therefore also relates to pharmaceutical compositionscomprising a compound as defined above and a pharmaceutically acceptablecarrier and/or adjuvant.

Further, the invention relates to compounds as defined above for use astherapeutically active substances, particularly as therapeutic activesubstances for the treatment and/or prophylaxis of diseases which aremediated by CETP. Examples of such diseases are atherosclerosis,peripheral vascular disease, dyslipidemia, hyperbetalipoproteinemia,hypoalphalipoproteinemia, hypercholesterolemia, hypertriglyceridemia,familial hypercholesterolemia, cardiovascular disorders, angina,ischemia, cardiac ischemia, stroke, myocardial infarction, reperfusioninjury, angioplastic restenosis, hypertension, and vascularcomplications of diabetes, obesity or endotoxemia.

In another embodiment, the invention relates to a method for thetreatment and/or prophylaxis of diseases which are mediated by CETP.Examples of such diseases are atherosclerosis, peripheral vasculardisease, dyslipidemia, hyperbetalipoproteinemia,hypoalphalipoproteinemia, hypercholesterolemia, hypertriglyceridemia,familial hypercholesterolemia, cardiovascular disorders, angina,ischemia, cardiac ischemia, stroke, myocardial infarction, reperfusioninjury, angioplastic restenosis, hypertension, and vascularcomplications of diabetes, obesity or endotoxemia. A method for thetreatment and/or prophylaxis of dyslipidemia is preferred. The inventionfurther relates to the use of compounds of formula I as defined abovefor the treatment and/or prophylaxis of diseases are mediated by CETP.Examples of such diseases are atherosclerosis, peripheral vasculardisease, dyslipidemia, hyperbetalipoproteinemia,hypoalphalipoproteinemia, hypercholesterolemia, hypertriglyceridemia,familial hypercholesterolemia, cardiovascular disorders, angina,ischemia, cardiac ischemia, stroke, myocardial infarction, reperfusioninjury, angioplastic restenosis, hypertension, and vascularcomplications of diabetes, obesity or endotoxemia. The use of compoundsof formula I as defined above for the treatment and/or prophylaxis ofdyslipidemia is preferred.

In addition, the invention relates to the use of compounds of formula Ias defined above for the preparation of medicaments for the treatmentand/or prophylaxis of diseases are mediated by CETP. Examples of suchdiseases are atherosclerosis, peripheral vascular disease, dyslipidemia,hyperbetalipoproteinemia, hypoalphalipoproteinemia,hypercholesterolemia, hypertriglyceridemia, familialhypercholesterolemia, cardiovascular disorders, angina, ischemia,cardiac ischemia, stroke, myocardial infarction, reperfusion injury,angioplastic restenosis, hypertension, and vascular complications ofdiabetes, obesity or endotoxemia. The use of compounds of formula I asdefined above for the preparation of medicaments for the treatmentand/or prophylaxis of dyslipidemia is preferred.

In addition, CETP inhibitors are useful in combination with anothercompound, said compound being an HMG-CoA reductase inhibitor, anmicrosomal triglyceride transfer protein (MTP)/ApoB secretion inhibitor,a PPAR activator, a bile acid reuptake inhibitor, a cholesterolabsorption inhibitor, a cholesterol synthesis inhibitor, a fibrate,niacin, an ion-exchange resin, an antioxidant, an ACAT inhibitor or abile acid sequestrant.

The invention therefore also relates to pharmaceutical compositionscomprising a compound of formula I as defined above in combination withan HMG-CoA reductase inhibitor, an microsomal triglyceride transferprotein (MTP)/ApoB secretion inhibitor, a PPAR activator, a bile acidreuptake inhibitor, a cholesterol absorption inhibitor, a cholesterolsynthesis inhibitor, a fibrate, niacin, an ion-exchange resin, anantioxidant, an ACAT inhibitor or a bile acid sequestrant, as well as apharmaceutically acceptable carrier and/or adjuvant.

The invention further relates to the use of compounds of formula I asdefined above in combination with an HMG-CoA reductase inhibitor, amicrosomal triglyceride transfer protein (MTP)/ApoB secretion inhibitor,a PPAR activator, a bile acid reuptake inhibitor, a cholesterolabsorption inhibitor, a cholesterol synthesis inhibitor, a fibrate,niacin, an ion-exchange resin, an antioxidant, an ACAT inhibitor or abile acid sequestrant for the treatment and/or prophylaxis of diseasessuch as atherosclerosis, peripheral vascular disease, dyslipidemia,hyperbetalipoproteinemia, hypoalphalipoproteinemia,hypercholesterolemia, hypertriglyceridemia, familialhypercholesterolemia, cardiovascular disorders, angina, ischemia,cardiac ischemia, stroke, myocardial infarction, reperfusion injury,angioplastic restenosis, hypertension, and vascular complications ofdiabetes, obesity or endotoxemia, as well as to the use of such acombination for the preparation of corresponding medicaments.

The compounds of formula I and their pharmaceutically acceptable saltspossess valuable pharmacological properties. Specifically, it has beenfound that the compounds of the present invention are inhibitors of thecholesteryl ester transfer protein (CETP).

The following tests were carried out in order to determine the activityof the compounds of formula I.

Activity of CETP inhibitors was determined using a buffer assay system.Partially purified CETP transferred radiolabeled cholesteryl ester fromHDL donor particles to biotin-labeled LDL acceptor particles. Thereaction was stopped by addition of streptavidin-coupled scintillationproximity assay (SPA) beads. These beads captured the biotinylatedacceptor particles and transferred radioactivity was measured. The assaysystem was purchased and performed according to manufacturer'srecommendations (Amersham Biosciences). Inhibitory activity of compoundswas determined as percentage of positive control activity containingCETP together with donor and acceptor particles. Serial dilution ofcompounds was performed in order to determine the IC₅₀ values.

Activity of the compounds was subsequently measured in the presence ofplasma using the same assay as described above except that the source ofCETP was human lipoprotein-deprived serum (LPDS). Inhibitory activity ofcompounds was determined as percentage of positive control activitycontaining all the assay components except compound. Serial dilution ofcompounds was performed in order to determine the IC₅₀ values.

Under the latter assay conditions, the compounds of the presentinvention exhibit IC₅₀ values within the range of about 1 nM to about100 μM, e.g., of about 1 nM to about 1 μM, e.g., of about 1 nM to about200 nM. The following table shows measured values for some selectedcompounds of the present invention.

IC₅₀ (nM) Compound B3 66848 Compound B104 1248 Compound B108 409

In vivo activity of the compounds of formula I were determined inhamster using the following protocol:

Male golden Syrian hamsters (6-week-old, 100-130 g) under standard chowdiet received compounds in the morning by oral gavage using appropriatevehicle, blood was taken 2 h later by retro-orbital bleeding underisofluran anaesthesia and 7 h later on sacrificed animals. Plasma wasseparated from blood using low speed centrifugation and CETP activitywas measured in plasma using the radioactive CETP activity assay asdescribed above except that diluted plasma replaced LPDS. In vivo CETPinhibition was expressed as CETP activity remaining in the plasma oftreated animals as compared to plasma CETP activity of placebo treatedanimals.

Efficacy of compounds in modulating plasma lipid levels can bedetermined in hamsters after 7 days of daily administration ofcompounds. Male hamsters are acclimated for 3-4 days to receive food asa paste made of 10 g chow and 10 g water per day. Compounds are thenmixed within this paste and a portion containing the proper amount ofcompounds is given every morning for 7 days. Alternatively compounds canbe given by oral gavage using the proper vehicle. Blood is taken beforecompound treatment by retro-orbital bleeding and at the end of thetreatment on sacrificed animals. Plasma is separated from blood by lowspeed centrifugation and selected organs are taken (e.g liver, fat,brain, etc.). Effects of compounds on plasma lipid levels are determinedby measuring total cholesterol, HDL-cholesterol, LDL-cholesterol andtriglyceride using calorimetric enzymatic assays (Roche Diagnostic GmbH,Mannheim, Germany). HDL-C, LDL-C and VLDL-C are e.g., quantified usingsize exclusion chromatography on superpose-6 column using SMART™ system(Pharmacia). Lipoprotein distribution is calculated assuming a Gaussiandistribution for each peak, using a non-linear, least-squarescurve-fitting procedure to calculate the area under the curve. Plasmasamples are also used to quantify CETP activity as described above.Compound concentration is also determined in plasma and selected tissuesas liver, fat, heart, muscle and brain.

Efficacy of compounds in modulating plasma lipid levels was alsodetermined in cholesterol/fat fed hamsters. The protocol is identical asdescribed above except that animals are fed with chow diet enriched with10% (w/w) saturated fat and 0.05% (w/w) cholesterol. Animals receivedthis high fat diet 2 weeks before starting compound administration andcontinued this diet throughout the study. The 2 weeks pre-treatmentinduced an increase in plasma cholesterol and triglyceride levelsallowing a better assessment of LDL-C and triglyceride lowering.

Efficacy of compounds in its ability to acutely raise HDL-C can beassessed in cynomolgus monkeys. Animals are fed with standard primatemaintenance diet. Compounds are formulated with appropriate vehicle andadministered to animals by oral gavage. Blood is taken before and atseveral time-points after compound administration (usually 30 min, 1 h,2 h, 4 h, 7 h and 24 h). Plasma is separated from blood by low speedcentrifugation and CETP activity and plasma lipids are quantified.Compound potency and efficacy can be assessed by measuring the HDL-Cincrease after this single-dose administration. In such pharmacodynamicmodel the extent together with the kinetics of the pharmacologic effectcan be assessed.

The compounds of formula I and their pharmaceutically acceptable saltsand esters can be used as medicaments, e.g. in the form ofpharmaceutical preparations for enteral, parenteral or topicaladministration. They can be administered, e.g., perorally, e.g. in theform of tablets, coated tablets, dragées, hard and soft gelatinecapsules, solutions, emulsions or suspensions, rectally, e.g. in theform of suppositories, parenterally, e.g. in the form of injectionsolutions or infusion solutions, or topically, e.g. in the form ofointments, creams or oils.

The production of the pharmaceutical preparations can be effected in amanner which will be familiar to any person skilled in the art bybringing the described compounds of formula I and their pharmaceuticallyacceptable, into a galenical administration form together with suitable,non-toxic, inert, therapeutically compatible solid or liquid carriermaterials and, if desired, usual pharmaceutical adjuvants.

Suitable carrier materials are not only inorganic carrier materials, butalso organic carrier materials. Thus, e.g., lactose, corn starch orderivatives thereof, talc, stearic acid or its salts can be used ascarrier materials for tablets, coated tablets, dragées and hard gelatinecapsules. Suitable carrier materials for soft gelatine capsules are,e.g., vegetable oils, waxes, fats and semi-solid and liquid polyols(depending on the nature of the active ingredient no carriers are,however, required in the case of soft gelatine capsules). Suitablecarrier materials for the production of solutions and syrups are, e.g.,water, polyols, sucrose, invert sugar and the like. Suitable carriermaterials for injection solutions are, e.g., water, alcohols, polyols,glycerol and vegetable oils. Suitable carrier materials forsuppositories are, e.g., natural or hardened oils, waxes, fats andsemi-liquid or liquid polyols. Suitable carrier materials for topicalpreparations are glycerides, semi-synthetic and synthetic glycerides,hydrogenated oils, liquid waxes, liquid paraffins, liquid fattyalcohols, sterols, polyethylene glycols and cellulose derivatives.

Usual stabilizers, preservatives, wetting and emulsifying agents,consistency-improving agents, flavor-improving agents, salts for varyingthe osmotic pressure, buffer substances, solubilizers, colorants andmasking agents and antioxidants come into consideration aspharmaceutical adjuvants.

The dosage of the compounds of formula I can vary within wide limitsdepending on the disease to be controlled, the age and the individualcondition of the patient and the mode of administration, and will, ofcourse, be fitted to the individual requirements in each particularcase. For adult patients a daily dosage of about 1 mg to about 1000 mg,especially about 1 mg to about 100 mg, comes into consideration.Depending on the dosage it is convenient to administer the daily dosagein several dosage units.

The pharmaceutical preparations conveniently contain about 0.1-500 mg,e.g., 0.5-100 mg, of a compound of formula I.

The following examples serve to illustrate the present invention in moredetail. They are, however, not intended to limit its scope in anymanner.

EXAMPLE A Film Coated Tablets

Ingredients Per tablet Kernel: Compound of formula (I) 10.0 mg  200.0mg  Microcrystalline cellulose 23.5 mg  43.5 mg  Lactose hydrous 60.0mg  70.0 mg  Povidone K30 12.5 mg  15.0 mg  Sodium starch glycolate 12.5mg  17.0 mg  Magnesium stearate 1.5 mg 4.5 mg (Kernel Weight) 120.0 mg 350.0 mg  Film Coat: Hydroxypropyl methyl cellulose 3.5 mg 7.0 mgPolyethylene glycol 6000 0.8 mg 1.6 mg Talc 1.3 mg 2.6 mg Iron oxide(yellow) 0.8 mg 1.6 mg Titanium dioxide 0.8 mg 1.6 mg

The active ingredient is sieved and mixed with microcrystallinecellulose and the mixture is granulated with a solution ofpolyvinylpyrrolidon in water. The granulate is mixed with sodium starchglycolate and magnesium stearate and compressed to yield kernels of 120or 350 mg respectively. The kernels are lacquered with an aqueoussolution/suspension of the above mentioned film coat.

EXAMPLE B Capsules

Ingredients Per capsule Compound of formula (I) 25.0 mg Lactose 150.0mg  Maize starch 20.0 mg Talc  5.0 mg

The components are sieved and mixed and filled into capsules of size 2.

EXAMPLE C Injection Solutions

Compound of formula (I) 3.0 mg Gelatin 150.0 mg Phenol 4.7 mg Sodiumcarbonate to obtain a final pH of 7 Water for injection solutions ad 1.0ml

EXAMPLE D Soft Gelatin Capsules

Capsule contents Compound of formula (I) 5.0 mg Yellow wax 8.0 mgHydrogenated Soya bean oil 8.0 mg Partially hydrogenated plant oils 34.0mg Soya bean oil 110.0 mg Weight of capsule contents 165.0 mg Gelatincapsule Gelatin 75.0 mg Glycerol 85% 32.0 mg Karion 83 8.0 mg (drymatter) Titanium dioxide 0.4 mg Iron oxide yellow 1.1 mg

The active ingredient is dissolved in a warm melting of the otheringredients and the mixture is filled into soft gelatin capsules ofappropriate size. The filled soft gelatin capsules are treated accordingto the usual procedures.

1. A compound of formula I

wherein R¹ is C₁-C₆alkyl, halo-C₁-C₆alkyl, halo-C₁-C₆alkoxy,C₃-C₈cycloalkyl, halo-C₃-C₈cycloalkyl or tri-C₁-C₆alkylsilyl; R² ishydrogen or a group

wherein R⁶ and R⁷ are independently hydrogen, C₁-C₆alkyl,halo-C₁-C₆alkyl, halogen, C₃-C₈cycloalkyl, OH or halo-C₁-C₆alkoxy; R⁸and R⁹ are independently hydrogen, C₁-C₆alkyl, halo-C₁-C₆alkyl, halogen,C₃-C₈cycloalkyl, OH or halo-C₁-C₆alkoxy; X is CR¹² or N; Y is CH or N;wherein X and Y are not N at the same time; R¹² is hydrogen, C₁-C₆alkyl,halo-C₁-C₆alkyl, halogen, C₃-C₈cycloalkyl, OH or halo-C₁-C₆alkoxy; R⁵ ishydrogen, C₁-C₆alkyl, halo-C₁-C₆alkyl, halogen, C₃-C₈cycloalkyl, OH orhalo-C₁-C₆alkoxy; R⁴ is hydrogen, or is C₁-C₆alkyl, halo-C₁-C₆alkyl,halogen, C₃-C₈cycloalkyl, OH or halo-C₁-C₆alkoxy when at least one ofR³, R⁵, R¹⁰ and R¹¹ is not hydrogen; A is CR¹⁰ or N; B is CR¹¹ or N; Dis CR³ or N; wherein —B=A- and -A=D- are not —N═N—; R³ is hydrogen,C₁-C₆alkyl, halo-C₁-C₆alkyl, halogen, C₃-C₈cycloalkyl, OH orhalo-C₁-C₆alkoxy; R¹⁰ is hydrogen, or is C₁-C₆alkyl, halo-C₁-C₆alkyl,halogen, C₃-C₈cycloalkyl, OH or halo-C₁-C₆alkoxy, when at least one ofR³, R⁴, R⁵ and R¹ is not hydrogen; R¹¹ is hydrogen or is C₁-C₆alkyl,halo-C₁-C₆alkyl, halogen, C₃-C₈cycloalkyl, OH or halo-C₁-C₆alkoxy, whenat least two of R³, R⁴, R⁵ and R¹⁰ are not hydrogen; wherein at leasttwo of R³, R⁴, R⁵, R¹⁰ and R¹¹ are not hydrogen; and n is 1, 2 or 3; andpharmaceutically acceptable salts thereof.
 2. The compound according toclaim 1 wherein R¹ is C₁-C₆alkyl, halo-C₁-C₆alkyl, C₃-C₈cycloalkyl,halo-C₃-C₈cycloalkyl or tri-C₁-C₆alkylsilyl.
 3. The compound accordingto claim 1 wherein R² is a group (a).
 4. The compound according to claim1 wherein R² is a group (b).
 5. The compound according to claim 1wherein R¹ is C₁-C₆alkyl, halo-C₁-C₆alkyl, halo-C₁-C₆alkoxy,C₃-C₈cycloalkyl, halo-C₃-C₈cycloalkyl or tri-C₁-C₆alkylsilyl; R² ishydrogen or a group

wherein R⁶ and R⁷ are independently hydrogen, C₁-C₆alkyl,halo-C₁-C₆alkyl, halogen, C₃-C₈cycloalkyl, OH or halo-C₁-C₆alkoxy; R⁸and R⁹ are independently hydrogen, C₁-C₆alkyl, halo-C₁-C₆alkyl, halogen,C₃-C₈cycloalkyl, OH or halo-C₁-C₆alkoxy; X is CR¹² or N; Y is CH or N;wherein X and Y are not N at the same time; R¹² is hydrogen, C₁-C₆alkyl,halo-C₁-C₆alkyl, halogen, C₃-C₈cycloalkyl, OH or halo-C₁-C₆alkoxy; R⁵ ishydrogen, C₁-C₆alkyl, halo-C₁-C₆alkyl, halogen, C₃-C₈cycloalkyl, OH orhalo-C₁-C₆alkoxy; R⁴ is hydrogen, or is C₁-C₆alkyl, halo-C₁-C₆alkyl,halogen, C₃-C₈cycloalkyl, OH or halo-C₁-C₆alkoxy when at least one ofR³, R⁵, R¹⁰ and R¹¹ is not hydrogen; A is CR¹⁰; B is CR¹¹ or N; D is CR³or N; R³ is hydrogen, C₁-C₆alkyl, halo-C₁-C₆alkyl, halogen,C₃-C₈cycloalkyl, OH or halo-C₁-C₆alkoxy; R¹⁰ is hydrogen, or isC₁-C₆alkyl, halo-C₁-C₆alkyl, halogen, C₃-C₈cycloalkyl, OH orhalo-C₁-C₆alkoxy, when at least one of R³, R⁴, R⁵ and R¹¹ is nothydrogen; R¹¹ is hydrogen or is C₁-C₆alkyl, halo-C₁-C₆alkyl, halogen,C₃-C₈cycloalkyl, OH or halo-C₁-C₆alkoxy, when at least two of R³, R⁴, R⁵and R¹⁰ are not hydrogen; wherein at least two of R³, R⁴, R⁵, R¹⁰ andR¹¹ are not hydrogen; and n is 1, 2 or 3; and pharmaceuticallyacceptable salts thereof.
 6. The compound according to claim 1 whereinR¹ is C₁-C₆alkyl, halo-C₁-C₆alkyl, halo-C₁-C₆alkoxy, C₃-C₈cycloalkyl,halo-C₃-C₈cycloalkyl or tri-C₁-C₆alkylsilyl; R² is hydrogen or a group

wherein R⁶ and R⁷ are independently hydrogen, C₁-C₆alkyl,halo-C₁-C₆alkyl, halogen, C₃-C₈cycloalkyl, OH or halo-C₁-C₆alkoxy; R⁸and R⁹ are independently hydrogen, C₁-C₆alkyl, halo-C₁-C₆alkyl, halogen,C₃-C₈cycloalkyl, OH or halo-C₁-C₆alkoxy; X is CR¹² or N; Y is CH or N;wherein X and Y are not N at the same time; R¹² is hydrogen, C₁-C₆alkyl,halo-C₁-C₆alkyl, halogen, C₃-C₈cycloalkyl, OH or halo-C₁-C₆alkoxy; R⁵ ishydrogen, C₁-C₆alkyl, halo-C₁-C₆alkyl, halogen, C₃-C₈cycloalkyl, OH orhalo-C₁-C₆alkoxy; R⁴ is hydrogen, or is C₁-C₆alkyl, halo-C₁-C₆alkyl,halogen, C₃-C₈cycloalkyl, OH or halo-C₁-C₆alkoxy when at least one ofR³, R⁵ and R¹¹ is not hydrogen; A is N; B is CR¹¹; D is CR³; R³ ishydrogen, C₁-C₆alkyl, halo-C₁-C₆alkyl, halogen, C₃-C₈cycloalkyl, OH orhalo-C₁-C₆alkoxy; R¹¹ is hydrogen or is C₁-C₆alkyl, halo-C₁-C₆alkyl,halogen, C₃-C₈cycloalkyl, OH or halo-C₁-C₆alkoxy, when at least two ofR³, R⁴, R⁵ and R¹⁰ are not hydrogen; wherein at least two of R³, R⁴, R⁵,R¹⁰ and R¹¹ are not hydrogen; and n is 1, 2 or 3; and pharmaceuticallyacceptable salts thereof.
 7. The compound according to claim 1 whereinR¹ is C₁-C₆alkyl, halo-C₁-C₆alkyl, halo-C₁-C₆alkoxy, C₃-C₈cycloalkyl,halo-C₃-C₈cycloalkyl or tri-C₁-C₆alkylsilyl; R² is hydrogen or a group

wherein R⁶ and R⁷ are independently hydrogen, C₁-C₆alkyl,halo-C₁-C₆alkyl, halogen, C₃-C₈cycloalkyl, OH or halo-C₁-C₆alkoxy; R⁸and R⁹ are independently hydrogen, C₁-C₆alkyl, halo-C₁-C₆alkyl, halogen,C₃-C₈cycloalkyl, OH or halo-C₁-C₆alkoxy; X is CR¹² or N; Y is CH or N;wherein X and Y are not N at the same time; R¹² is hydrogen, C₁-C₆alkyl,halo-C₁-C₆alkyl, halogen, C₃-C₈cycloalkyl, OH or halo-C₁-C₆alkoxy; R⁵ ishydrogen, C₁-C₆alkyl, halo-C₁-C₆alkyl, halogen, C₃-C₈cycloalkyl, OH orhalo-C₁-C₆alkoxy; R⁴ is hydrogen, or is C₁-C₆alkyl, halo-C₁-C₆alkyl,halogen, C₃-C₈cycloalkyl, OH or halo-C₁-C₆alkoxy when at least one ofR³, R⁵, R¹⁰ and R¹¹ is not hydrogen; A is CR¹⁰; B is CR¹¹ or N; D isCR³; R³ is hydrogen, C₁-C₆alkyl, halo-C₁-C₆alkyl, halogen,C₃-C₈cycloalkyl, OH or halo-C₁-C₆alkoxy; R¹⁰ is hydrogen, or isC₁-C₆alkyl, halo-C₁-C₆alkyl, halogen, C₃-C₈cycloalkyl, OH orhalo-C₁-C₆alkoxy, when at least one of R³, R⁴, R⁵ and R¹¹ is nothydrogen; R¹¹ is hydrogen or is C₁-C₆alkyl, halo-C₁-C₆alkyl, halogen,C₃-C₈cycloalkyl, OH or halo-C₁-C₆alkoxy, when at least two of R³, R⁴, R⁵and R¹⁰ are not hydrogen; wherein at least two of R³, R⁴, R⁵, R¹⁰ andR¹¹ are not hydrogen; and n is 1, 2 or 3; and pharmaceuticallyacceptable salts thereof.
 8. The compound according to claim 1 whereinR¹ is C₁-C₆alkyl; R² is a group

wherein R⁸ and R⁹ are independently hydrogen, halo-C₁-C₆alkyl, halogen,C₃-C₈cycloalkyl or halo-C₁-C₆alkoxy; X is CR¹¹; Y is CH; R¹² ishydrogen, halogen or C₃-C₈cycloalkyl; R⁵ is hydrogen or halogen; R⁴ isC₁-C₆alkyl, halo-C₁-C₆alkyl or halogen; A is CR¹⁰; B is CR¹¹ or N; D isCR³; R³ is hydrogen; R¹⁰ is halo-C₁-C₆alkyl or halogen; R¹¹ is hydrogen;and n is 1, 2 or 3; and pharmaceutically acceptable salts thereof.
 9. Aprocess for the production of a compound of formula I according to claim1 which process comprises reacting an acid derivative, a compound offormula II

wherein R⁴, R⁵, A, B and D have the meanings as defined in claim 1 and Wis hydroxy, OLi, ONa, OK or halogen, with a secondary amine derivative,a compound of formula III

wherein R¹, R² and n have the meanings as defined in claim 1 andoptionally converting the resulting compound into a pharmaceuticallyacceptable salt.
 10. The compound of claim 5 wherein R² is


11. The compound of claim 5 wherein R² is


12. The compound of claim 6 wherein R² is


13. The compound of claim 6 wherein R² is


14. The compound of claim 7 wherein R² is


15. The compound of claim 7 wherein R² is


16. A pharmaceutical composition comprising a compound according toclaim 1 and a pharmaceutically acceptable carrier or adjuvant or mixturethereof.